Methods for treating hepatitis C

ABSTRACT

The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.11/331,180, filed Jan. 13, 2006, which is a continuation-in-part ofapplication Ser. No. 11/180,961, filed Jul. 14, 2005, and ofInternational Application No. PCT/US2005/024881, filed Jul. 14, 2005,both of which applications claim the benefit of U.S. ProvisionalApplication No. 60/587,487, filed Jul. 14, 2004, U.S. ProvisionalApplication No. 60/634,979, filed Dec. 13, 2004, U.S. ProvisionalApplication No. 60/645,586, filed Jan. 24, 2005, U.S. ProvisionalApplication No. 60/665,349, filed Mar. 28, 2005, and U.S. ProvisionalApplication No. 60/675,440, filed Apr. 28, 2005; this application alsoclaims the benefit of U.S. Provisional Application No. 60/758,527, filedJan. 13, 2006, the entire contents of which applications areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides compounds, pharmaceutical compositions,and methods of using such compounds or compositions for treatinginfection by a virus, or for affecting viral IRES activity.

BACKGROUND OF THE INVENTION

An estimated 170 million people worldwide are reported to be infectedwith hepatitis C virus (HCV), the causative agent of hepatitis C.Seventy to eighty percent of HCV infections lead to chronic liverinfection, which in turn may result in severe liver disease, includingliver fibrosis, cirrhosis, and hepatocellular carcinoma (115).

HCV constitutes the Hepacivirus genus of the family Flaviviridae (106),and contains a positive-stranded 9.6 kb RNA genome. The features of theHCV genome include a 5′-untranslated region (UTR) that encodes aninternal ribosome entry site (IRES) that directs the translation of asingle long open reading frame (ORF) encoding a polyprotein of 3,010amino acids. The HCV ORF is followed by a 3′-UTR of variable length,depending on the HCV variant, that encodes the sequences required forthe initiation of antigenomic strand synthesis (79).

The HCV IRES and 3′-UTR both encode regions of RNA structures that arerequired for genome translation and replication. The HCV polyprotein isposttranslationally processed into at least 10 mature viral proteins,including the structural proteins core (putative nucleocapsid), E1 andE2 and the nonstructural (NS) proteins NS2 to NS5B.

Three distinct elements have been shown to be involved in HCVIRES-mediated translation: (1) integrity of the global structure of HCVIRES, (2) the 3′-terminal region of the HCV genome; and (3) trans-actingcellular factors that interact with the HCV IRES element and assist intranslation initiation (35).

The initiation of protein synthesis in eukaryotic cells predominantlyfollows the 5′ cap-dependent, first AUG rule (61). However, anincreasing number of viral (6, 12, 28, 31a, 50, 95, 97, 98, 105, 128)and cellular mRNAs (18, 39, 45, 78, 91, 130) have been shown to use anIRES element to direct translation initiation. In 1992, an IRES elementwas reported in the 5′ UTR of the HCV RNA genome (129), indicating thatsynthesis of the viral protein is initiated in a cap-independentfashion.

A bicistronic expression system can be used to define and evaluate thefunction of IRES elements. This test system harbors two differentreporter genes in which the 5′-proximal reporter gene is expressed by acap dependent translation mechanism while the second reporter isexpressed only if an upstream sequence inserted in the intergenic spacecontains an IRES sequence element. Using this system, a putative IRES inthe HCV 5′ UTR was unambiguously demonstrated to function as an IRESinvolved in translational control of viral proteins (133). In vitrotranslation, RNA transfection, and mutagenesis studies provided furtherevidence that the HCV 5′ UTR contains an IRES element (23, 41, 42, 108,129, 132, 133, 134). Both in vitro and cell-based studies demonstratedthat the HCV IRES guides cellular translation initiation factors to aninternal site of the viral RNA (56, 58, 120), thus functionallydemonstrating the HCV IRES activity. Taken together, these resultsdemonstrate that the HCV 5′-UTR contains an IRES element that plays anactive and crucial role in the mechanism of internal initiation for HCVprotein translation.

The IRES is one of the most conserved regions of the HCV genome,reflecting its essential nature for viral replication and proteinsynthesis (13, 118, 122). Although both 5′ and 3′ sequences of the IRESappear to play a role in the control of initiation of translation (42,109, 110, 113, 136), the minimal sequence requirement for HCV IRESfunction has been mapped to a region between nucleotides 44-354 (40).

Biochemical probing and computer modeling indicate that the HCV IRES andits 5′ sequence is folded into a distinct structure that consists offour major domains and a pseudoknot (11, 42, 122). Domain I contains asmall stem-loop structure that does not appear to be a functional partof the IRES element while domains II, III, and IV contain the HCV IRESactivity (43, 111). The relationships between secondary and tertiarystructures of the HCV IRES and their function have recently beenestablished (5, 55, 56, 99, 124). Both domains II and III consist ofmultiple stems, loops, and bulges and are important for IRES activity(23, 40, 51, 52, 54, 56, 64, 74, 75, 93, 107, 108, 110, 124, 127, 131,139, 141, 142). Domain II can induce conformational changes on theribosome that have been implicated in the decoding process (124). DomainIII has the highest degree of structural conservation among thedifferent HCV strains. It comprises the core of the flavivirus IRES andhas 6 subdomains (40). Various studies have shown that subdomain IIIdforms complex secondary/tertiary structures and is critical forinitiation activity (55, 56, 57, 124, 129). Domain IV has one stem-loopthat spans the initiation codon and is specific for the HCV IRES (41,122), but the precise role of domain IV in IRES activity remainscontroversial (41, 112).

The role of the HCV IRES is to position the translational machinery nearan internal initiator codon in the viral mRNA. The translationinitiation mechanism of the HCV and other viral IRES differssignificantly from that of 5′-cap-dependent translation initiation (7,21, 31, 35, 61, 71, 72, 81, 88, 96, 114, 123). Most cellular cappedmRNAs utilize a number of initiation factors (eIFs) that are requiredfor the translation initiation process. The initial steps of the processrequire proteins that interact with the 5′ cap structure and recruit the40S ribosomal subunit to the cap-proximal region of mRNA. This complexthen scans 3′ of the cap, until reaching an AUG codon at whichtranslation will initiate (21, 114). However, in the case of HCV, theIRES functionally replaces the 5′ cap structure, allowing the 40Sribosomal subunit and eIF3 to bind directly to the RNA. Subdomain IIIdof the HCV IRES harbors the binding site for the 40S ribosomal subunitand the only initiation factors required for translation initiation areeIF2, eIF3, and eIF4E (15, 58, 94, 100, 120, 124).

The polypyrimidine track-binding protein (PTB) and La autoantigen arenoncanonical translation initiation factors that bind to and enhance HCVIRES activity (1, 2, 3, 4, 5, 30, 48, 49, 53). PTB, a 57-kDa proteininvolved in RNA splicing, is also necessary for efficient IRES-mediatedtranslation initiation of picornavirus mRNA, and some cellular mRNAs(10, 11, 36, 53, 59, 89, 92). The La autoantigen, a 52 kDadouble-stranded RNA unwinding protein, also increases the activity ofpoliovirus and cellular IRES (38, 85, 86). Other cellular factorsinvolved in HCV IRES-mediated translation initiation include proteasomeα-subunit PSMA7 (62), ribosomal protein S5 (26), ribosomal protein S9(24, 25, 100), and hnRNPL (33). However, the role of these RNA-bindingproteins in HCV IRES-mediated initiation of translation is unclear.Recently, it was reported that the activity of interferon (IFN) αagainst HCV replication might target HCV IRES-mediated translationinitiation by causing a reduction of La protein levels (117) Some HCVproteins, such as NS5A, core and NS4A/4B, also reported to be involvedin the HCV IRES function (143-146). Thus, an inhibitor that blocksinteraction between the IRES and the noncanonical factors mightefficiently inhibit HCV replication and lack cytotoxicity.

Currently, only interferon (IFN) α and the nucleoside analogueribavirin, in combination, are marketed for the treatment of HCVinfection. However, these two agents are immunomodulators and havelimited efficacy, relatively high toxicity, and high cost (80, 83, 84,138). Although the treatment outcome is variable among the six major HCVgenotypes, only about one-half of all treated patients respond totherapy, suggesting that the virus encodes protein products that maydirectly or indirectly attenuate the antiviral action of IFN. IFNs arenaturally produced in response to virus infection, and cellular exposureto IFN leads to the induced expression of a variety of IFN-stimulatedgenes (ISGs), many of which have an antiviral function. ISG action canlimit virus replication at multiple points within the replicative cycle.

There remains a need for an alternative means of treating patientsafflicted with HCV. Specifically, a need exists for novel antiviraldrugs, for example, that have no cross-resistance with existingtreatment modalities, and which demonstrate synergy with other anti-HCVagents.

All documents referred to herein are incorporated by reference into thepresent application as though fully set forth herein.

SUMMARY OF THE INVENTION

The present invention provides compounds, pharmaceutical compositions,and methods of using such compounds or compositions for treatinginfection by a virus, or for affecting viral IRES activity.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the HCV-PV chimera construct. The cloverleaf-like RNAstructure of PV, an essential cis-acting replication signal ending withthe genome-linked protein VPg, is located at the 5′ end of the genome.The solid (HCV) and open (PV) boxes depict open reading frames encodingviral polypeptides. The position of the HCV core fragment (the first 123amino acids) gene is denoted by Δ Core. Overall, the HCV-specificsequence in the HCV-PV spans from nucleotides 18 to 710 (139).

DETAILED DESCRIPTION OF THE INVENTION A. COMPOUNDS OF THE INVENTION

One aspect of the invention relates to a compound of formula I

-   wherein:-   X is:-   hydrogen;-   a nitro group;-   a cyano group;-   a —COR_(a) group, where R_(a) is:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or a halogen, or

a dialkyl-amino;

-   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;-   a formyl group;-   a C₆ to C₈ aryl optionally substituted with an alkoxy; or-   a 5 or 6-membered heteroaryl optionally substituted with:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or one or morehalogen(s), or

a 5 to 6 membered heteroaryl;

-   Y is:-   a hydrogen;-   a haloalkyl;-   a halogen;-   an amino optionally substituted with one or more C₁ to C₆ alkyl(s);-   a benzofuran;-   a benzothiophene;-   a dibenzofuran;-   a dibenzothiophene;-   a benzothiazole;-   a naphthalene;-   an indole, optionally substituted on the nitrogen with a C₁ to C₆    alkyl;    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined    above, or an —SO₂R_(x), where R_(x) is as defined above; or    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;-   a —NHCOR_(e) group, where R_(e) is:

a C₁ to C₆ alkyl;

a C₆ to C₈ aryl optionally substituted with:

-   -   a C₁ to C₆ alkyl,    -   an alkoxy,    -   a cyano group,    -   a nitro group, or    -   a halogen;

-   a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;

-   a —NR_(g)R_(h) group, where R_(g) is hydrogen or a C₁ to C₆ alkyl    and R_(h) is hydrogen or a C₆ to C₈ aryl optionally substituted with    an alkoxy;

-   a C₁ to C₆ alkyl;

-   a 5 or 6 membered heteroaryl, optionally substituted with:

a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,

a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where R_(x) isas defined above, or

an amino group;

-   a 5 or 6 membered heterocycle optionally substituted with:

a —COOR_(x) group, where R_(x) is as defined above, or

a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a C₆ to C₈ aryl, optionally substituted with one or more of the    following:

an alkoxy, optionally substituted with:

-   -   an alkoxy,    -   a hydroxy,    -   one or more halogen(s),    -   a 5 or 6 membered heterocycle, optionally substituted with:        -   a C₁ to C₆ alkyl, or        -   a hydroxy,    -   an amino group optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and        R_(i) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —NR_(j)COR_(k) group, where R_(k) is:        -   a C₁ to C₆ alkyl,        -   a hydrogen, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),    -   and R_(j) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —N═N⁺═N⁻ group, or    -   a —COR₁, where R₁ is a 5 or 6 membered heterocycle optionally        substituted with a hydroxy,

an amino optionally substituted with one or more C₁ to C₆ alkyl(s),

a nitro group,

a C₁ to C₆ alkyl group, optionally substituted with:

-   -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or    -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,

a haloalkoxy,

a halogen,

a hydroxy,

a —COOR_(x) group, where R_(x) is as defined above,

a —COR_(x) group, where R_(m) is:

-   -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), where the one or more C₁ to C₆ alkyl(s) is/are        optionally substituted with:        -   a hydroxy        -   a 5 or 6 membered heterocycle,        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),        -   an alkoxy,    -   a 3 to 7 membered heterocycle, optionally substituted with a C₁        to C₆ alkyl, optionally substituted with a dialkyl-amino,    -   a —NHR_(n) group, where R_(n) is:        -   a —CH₂CONH₂, or        -   a C₆ to C₈ aryl optionally substituted with:            -   an alkyl,            -   one or more halogen(s),            -   a nitro group, or            -   one or more alkoxy(s),

a —NR_(o)COR_(p) group, where R_(p) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   an alkoxy, or        -   a C₆ to C₈ aryl,    -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with a halogen,    -   a 5 or 6 membered heteroaryl optionally substituted with one or        more C₁ to C₆ alkyl(s),    -   a hydrogen,

and where R_(o) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a haloalkyl,    -   a haloalkoxy, or    -   a —COR_(x) group, where R_(x) is as defined above,

and where R_(r) is:

-   -   a C₆ to C₈ aryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a C₁ to C₆ alkyl optionally substituted with one or more of the        following:        -   a halogen,        -   an alkylene,        -   a C₆ to C₈ aryl, and/or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a —COOR_(x) group, where R_(x) is as defined above,

a —NR_(t)COOR_(u) group, where R_(u) is:

-   -   a C₁ to C₁₂ alkyl, optionally substituted with:        -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆ alkyl            or an alkoxy,        -   an alkylene,        -   an alkoxy,        -   an alkyne,        -   a halogen, or        -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with:        -   an alkoxy,        -   a halogen, or        -   a C₁ to C₆ alkyl, or    -   a 5 or 6 membered heterocycle,

and R_(t) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(v)SO₂R_(w) group, where R_(v) is:

-   -   a hydrogen,    -   a —COR_(x), where R_(x) is as defined above, or    -   a C₁ to C₆ alkyl, optionally substituted with:        -   a halogen,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a —OCOR_(x) group, where R_(x) is as defined above,        -   a hydroxy, or        -   an alkoxy,

and where R_(w) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   a haloalkyl,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle,    -   a C₂ to C₆ alkylene,    -   an alkyl- or dialkyl-amino optionally substituted with a        halogen,    -   a 5 or 6 membered heterocycle, or    -   a 5 or 6 membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a 5 or 6 membered heterocycle, or            optionally substituted with a C₁ to C₆ alkyl, where R_(y) is            a C₁ to C₆ alkyl or hydrogen,    -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally        substituted with a C₆ to C₈ aryl,    -   a —SR_(x) group, where R_(x) is as defined above,    -   a —SO₂R_(aa) group, where R_(aa) is:        -   a C₁ to C₆ alkyl,        -   an amino group,        -   an alkyl- or dialkyl-amino group optionally substituted with            a hydroxy or a —COOR_(x) group, where R_(x) is as defined            above,        -   a 5 or 6 membered heteroaryl,    -   a C₆ to C₈ aryl, and/or    -   a —NHR_(bb) group, where R_(bb) is:        -   a —C(═S)NH₂ group, or        -   a —PO(OR_(x))₂ group, where R_(x) is as defined above;            group, where R_(cc) is:    -   a naphthalene,    -   a 5 or 6 membered heteroaryl,    -   a C₆ to C₈ aryl, optionally substituted with one or more of the        following:        -   an alkoxy,        -   a hydroxy,        -   a halogen,        -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,        -   an amino optionally substituted with one or more C₁ to C₆            alkyls,        -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,        -   a —NR_(cc)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen            or a C₁ to C₆ alkyl, optionally substituted with a halogen,            and R_(ff) is:            -   a hydrogen,            -   a haloalkyl,            -   a haloalkoxy,            -   a C₁ to C₆ alkyl, or            -   a —COR_(x), where R_(x) is as defined above,        -   a —NR_(gg)COR_(hh) group, where R_(hh) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl optionally substituted with:                -   an alkoxy,                -   a halogen, or                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls, where the alkyls are optionally substituted                with a halogen,            -   a 5 or 6 membered heterocycle,            -   a 5 or 6 membered heteroaryl,        -   and R_(gg) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a haloalkyl,            -   a haloalkoxy, or            -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl,        -   5 or 6 membered heterocycle groups,        -   an amino optionally substituted with one or more C₁ to C₆            alkyls, and/or        -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above,            and R_(ii) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a haloalkyl,            -   a haloalkoxy,            -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:

-   a hydrogen;

-   a C₁ to C₆ alkyl optionally substituted with:

an alkoxy,

one or more halogen(s), or

a C₆ to C₈ aryl;

-   a C₂ to C₆ alkylene;-   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or more    C₁ to C₆ alkyl(s);-   a —COOR_(x) group, where R_(x) is as defined above; or-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:-   a hydrogen;-   a hydroxy;-   a halogen;-   a haloalkyl;-   a nitro group;-   a 5 or 6 membered heteroaryl;-   a 5 or 6 membered heterocycle;-   an alkoxy optionally substituted with:

one or more halogen(s),

a C₆ to C₈ aryl, or

a 5 or 6 membered heterocycle;

-   a C₆ to C₈ aryl optionally substituted with an alkoxy;-   a —COR_(x) group, where R_(x) is as defined above;-   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or a 5    or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:-   R₂ is:-   a nitro group;-   a hydrogen;-   a halogen;-   a hydroxy group;-   a C₁ to C₆ alkyl group, optionally substituted with one or more    halogen(s);-   an amino group;-   an alkoxy group optionally substituted with:

one or more halogen(s),

an —OCOR_(x) group, where R_(x) is as defined above,

a dialkyl-amino optionally substituted with an alkoxy,

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl,

a 5 or 6 membered heteroaryl group, or

a C₆ to C₈ aryl group;

-   a —COOR_(x) group, where R_(x) is as defined above;-   a haloalkyl;-   an amide group optionally substituted with:

a hydroxy group, or

a C₆ to C₈ aryl;

-   a 5 or 6 membered heteroaryl;-   a —OCOR_(x) group, where R_(x) is as defined above;-   a —NHCOR_(jj) group, where R_(jj) is:

an alkoxy, or

an amino optionally substituted with one or more C₁ to C₆ alkyl(s);

-   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;

a —NHSO₂R_(x) group, where R_(x) is as defined above; or

R₂ joins together with R₁ to form:

-   R₃ is:-   a hydrogen; or-   CH₂OCOR_(x), and R_(x) is as defined above;-   or a pharmaceutically acceptable salt thereof

In some embodiments of formula I,

-   X is:-   a nitro group;-   a cyano group;-   a —COR_(a) group, where R_(a) is:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or a halogen, or

a dialkyl-amino;

-   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;-   a formyl group;-   a C₆ to C₈ aryl optionally substituted with an alkoxy; or-   a 5 or 6-membered heteroaryl optionally substituted with:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or one or morehalogen(s), or

a 5 to 6 membered heteroaryl;

-   Y is:-   a haloalkyl;-   a halogen;-   an amino optionally substituted with one or more C₁ to C₆ alkyl(s);-   a benzofuran;-   a benzothiophene;-   a dibenzofuran;-   a dibenzothiophene;-   a benzothiazole;-   a naphthalene;-   an indole, optionally substituted on the nitrogen with a C₁ to C₆    alkyl;    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined    above, or an —SO₂R_(x), where R_(x) is as defined above;    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;-   a —NHCOR_(e) group, where R_(e) is:

a C₁ to C₆ alkyl;

a C₆ to C₈ aryl optionally substituted with:

-   -   a C₁ to C₆ alkyl,    -   an alkoxy,    -   a cyano group,    -   a nitro group, or    -   a halogen;

-   a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;

-   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a hydrogen    and R_(h) is a C₆ to C₈ aryl optionally substituted with an alkoxy;

-   a C₁ to C₆ alkyl;

-   a 5 or 6 membered heteroaryl, optionally substituted with:

a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,

a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where R_(x) isas defined above, or

an amino group;

-   a 5 or 6 membered heterocycle optionally substituted with:

a —COOR_(x) group, where R_(x) is as defined above, or

a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a C₆ to C₈ aryl, optionally substituted with one or more of the    following:

an alkoxy, optionally substituted with:

-   -   an alkoxy,    -   a hydroxy,    -   one or more halogen(s),    -   a 5 or 6 membered heterocycle, optionally substituted with:        -   a C₁ to C₆ alkyl, or        -   a hydroxy,    -   an amino group optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and        R_(i) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —NR_(j)COR_(k) group, where R_(k) is:        -   a C₁ to C₆ alkyl,        -   a hydrogen, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),    -   and R_(j) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —N═N⁺═N⁻ group, or    -   a —COR₁, where R₁ is a 5 or 6 membered heterocycle optionally        substituted with a hydroxy,

an amino optionally substituted with one or more C₁ to C₆ alkyl(s),

a C₁ to C₆ alkyl group, optionally substituted with:

-   -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or    -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,

a haloalkoxy,

a halogen,

a hydroxy,

a —COOR_(x) group, where R_(x) is as defined above,

a —COR_(m) group, where R_(m) is:

-   -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), where the one or more C₁ to C₆ alkyl(s) is/are        optionally substituted with:        -   a hydroxy        -   a 5 or 6 membered heterocycle,        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),        -   an alkoxy,    -   a 3 to 7 membered heterocycle, optionally substituted with a C₁        to C₆ alkyl, optionally substituted with a dialkyl-amino,    -   a —NHR_(n) group, where R_(n) is:        -   a —CH₂CONH₂, or        -   a C₆ to C₈ aryl optionally substituted with:            -   an alkyl,            -   one or more halogen(s),            -   a nitro group, or            -   one or more alkoxy(s),

a —NR_(o)COR_(p) group, where R_(p) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   an alkoxy, or        -   a C₆ to C₈ aryl,    -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with a halogen,    -   a 5 or 6 membered heteroaryl optionally substituted with one or        more C₁ to C₆ alkyl(s),    -   a hydrogen,

and where R_(o) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —N_(q)CONR_(q)R_(f) group, where R_(q) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a haloalkyl,    -   a haloalkoxy, or    -   a —COR_(x) group, where R_(x) is as defined above,

and where R_(f) is:

-   -   a C₆ to C₈ aryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a C₁ to C₆ alkyl optionally substituted with one or more of the        following:        -   a halogen,        -   an alkylene,        -   a C₆ to C₈ aryl, and/or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a —COOR_(x) group, where R_(x) is as defined above,

a —NR_(t)COOR_(u) group, where R_(u) is:

-   -   a C₁ to C₁₂ alkyl, optionally substituted with:        -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆ alkyl            or an alkoxy,        -   an alkylene,        -   an alkoxy,        -   an alkyne,        -   a halogen, or        -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with:        -   an alkoxy,        -   a halogen, or        -   a C₁ to C₆ alkyl, or    -   a 5 or 6 membered heterocycle,

and R_(t) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(v)SO₂R_(w) group, where R_(v) is:

-   -   a hydrogen,    -   a —COR_(x), where R_(x) is as defined above, or    -   a C₁ to C₆ alkyl, optionally substituted with:        -   a halogen,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a —OCOR_(x) group, where R_(x) is as defined above,        -   a hydroxy, or        -   an alkoxy,

and where R_(w) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   a haloalkyl,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle,        -   a C₂ to C₆ alkylene,    -   an alkyl- or dialkyl-amino optionally substituted with a        halogen,    -   a 5 or 6 membered heterocycle, or    -   a 5 or 6 membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a 5 or 6 membered heterocycle, or            optionally substituted with a C₁ to C₆ alkyl, where R_(y) is            a C₁ to C₆ alkyl or hydrogen,

where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally substituted witha C₆ to C₈ aryl,

a —SR_(x) group, where R_(x) is as defined above,

a —SO₂R_(aa) group, where R_(aa) is:

-   -   a C₁ to C₆ alkyl,    -   an amino group,    -   an alkyl- or dialkyl-amino group optionally substituted with a        hydroxy    -   or a —COOR_(x) group, where R_(x) is as defined above,    -   a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, and/or

a —NHR_(bb) group, where R_(bb) is:

-   -   a —C(═S)NH₂ group, or    -   a —PO(OR_(x))₂ group, where R_(x) is as defined above;        where R_(cc) is:

a naphthalene,

a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing:

-   -   an alkoxy,    -   a hydroxy,    -   a halogen,    -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,    -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen or a        C₁ to C₆ alkyl, optionally substituted with a halogen, and        R_(ff) is:        -   a hydrogen,        -   a haloalkyl,        -   a haloalkoxy,        -   a C₁ to C₆ alkyl, or        -   a —COR_(x), where R_(x) is as defined above,    -   a —NR_(gg)COR_(hh) group, where R_(hh) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl optionally substituted with:            -   an alkoxy,            -   a halogen, or            -   an amino optionally substituted with one or more C₁ to                C₆ alkyl(s),        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),        -   where the one or more C₁ to C₆ alkyl(s) is/are optionally            substituted with a halogen,        -   a 5 or 6 membered heterocycle,        -   a 5 or 6 membered heteroaryl,    -   and R_(gg) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a haloalkoxy, or        -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl,    -   5 or 6 membered heterocycle groups,    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), and/or    -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above, and        R_(ii) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a haloalkoxy,        -   a —COR_(e) group, where R_(x) is as defined above;

-   Z is:

-   a C₁ to C₆ alkyl optionally substituted with:

an alkoxy,

one or more halogen(s), or

a C₆ to C₈ aryl;

-   a C₂ to C₆ alkylene;-   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or more    C₁ to C₆ alkyl(s);-   a —COOR_(x) group, where R_(x) is as defined above; or-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:-   a hydrogen;-   a hydroxy;-   a halogen;-   a haloalkyl;-   a nitro group;-   a 5 or 6 membered heteroaryl;-   a 5 or 6 membered heterocycle;-   an alkoxy optionally substituted with:

one or more halogen(s),

a C₆ to C₈ aryl, or

a 5 or 6 membered heterocycle;

-   a C₆ to C₈ aryl optionally substituted with an alkoxy;-   a —COR_(x) group, where R_(x) is as defined above;-   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or a 5    or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:-   R₂ is:-   a nitro group;-   a hydrogen;-   a halogen;-   a hydroxy group;-   a C₁ to C₆ alkyl group, optionally substituted with one or more    halogen(s);-   an ammo group;-   an alkoxy group optionally substituted with:

one or more halogen(s),

an —OCOR_(x) group, where R_(x) is as defined above,

a dialkyl-amino optionally substituted with an alkoxy,

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl,

a 5 or 6 membered heteroaryl group, or

a C₆ to C₈ aryl group;

-   a —COOR_(x) group, where R_(x) is as defined above;-   a haloalkyl;-   an amide group optionally substituted with:

a hydroxy group, or

a C₆ to C₈ aryl;

-   a 5 or 6 membered heteroaryl;-   a —OCOR_(x) group, where R_(x) is as defined above;-   a —NHCOR_(jj) group, where R_(jj) is:

an alkoxy, or

an amino optionally substituted with one or more C₁ to C₆ alkyl(s);

-   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;-   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:-   R₃ is:-   a hydrogen; or-   —CH₂OCOR_(x), and R_(x) is as defined above;-   provided that when X is phenyl substituted with alkoxy, Y is phenyl,    R is hydrogen, R₁ is a halogen, R₂ is hydrogen, and R₃ is hydrogen,    and-   provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is    alkyl, R is hydrogen, R₁ is hydrogen or hydroxy, R₂ is hydrogen or    hydroxy, and R₃ is hydrogen, then Z is:-   a C₁ to C₆ alkyl substituted with:

an alkoxy,

one or more halogen(s), or

a C₆ to C₈ aryl;

-   a C₂ to C₆ alkylene;-   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or more    C₁ to C₆ alkyl(s);-   a —COOR_(x) group, where R_(x) is as defined above; or    or a pharmaceutically acceptable salt thereof.

In some embodiments, X is a nitro group or a cyano group. In otherembodiments, X is a cyano group.

In some embodiments, Y is a C₆ to C₈ aryl, optionally substituted withone or more of the following:

an amino optionally substituted with one or more C₁ to C₆ alkyl(s),

a C₁ to C₆ alkyl group, optionally substituted with a —NHSO₂R_(x) group,

a —NR_(o)COR_(p) group, where R_(p) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen, or        -   a C₆ to C₈ aryl, or    -   a 5 or 6 membered heterocycle,

and where R_(o) is a hydrogen,

a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:

-   -   a hydrogen, or    -   a C₁ to C₆ alkyl,

and where R_(f) is a C₁ to C₆ alkyl optionally substituted with one ormore of the following:

-   -   a halogen,    -   an alkylene, or    -   a C₆ to C₈ aryl,

a —NR_(t)COOR_(u) group, where R_(u) is:

-   -   a C₁ to C₁₂ alkyl, optionally substituted with:        -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆ alkyl            or an alkoxy,        -   an alkylene,        -   an alkoxy,        -   an alkyne,        -   a halogen, or        -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with an alkoxy,    -   a 5 or 6 membered heterocycle,

and where R_(t) is:

-   -   a hydrogen, or    -   a C₁ to C₆ alkyl,

a —NR_(v)SO₂R_(w) group, where R_(v) is a hydrogen, and where R_(w) is aC₁ to C₆ alkyl optionally substituted with a halogen;

where R_(z) is a C₁ to C₆ alkyl, and/or

a —NHR_(bb) group, where R_(bb) is a —PO(OR_(x))₂ group.

In further embodiments, Y is a C₆ to C₈ aryl substituted with:

a —NR_(q)CONR_(q)R_(r) group,

a —NR_(t)COOR_(u) group,

a —NR_(v)SO₂R_(w) group, or

a —NHR_(bb) group, where R_(bb) is a —PO(OR_(x))₂ group.

The C₆ to C₈ aryl may be substituted at the para, meta and/or orthoposition(s). In some embodiments, the C₆ to C₈ aryl is phenyl. In otherembodiments, the C₆ to C₈ aryl is phenyl substituted at the paraposition.

In some embodiments, Y is phenyl substituted with a —NR_(q)CONR_(q)R_(r)group at the para position. In other embodiments, Y is phenylsubstituted with a —NR_(t)COOR_(u) group at the para position. In yetother embodiments, Y is phenyl substituted with a —NR_(v)SO₂R_(w) groupat the para position. In yet other embodiments, Y is phenyl substitutedwith a —NHPO(OR_(x))₂ group at the para position.

In some embodiments, Z is:

-   a C₁ to C₆ alkyl optionally substituted with

an alkoxy, or

one or more halogen(s), or

-   a C₂ to C₆ alkylene.

In other embodiments, Z is a C₁ to C₆ alkyl. In yet other embodiments, Zis a a C₂ to C₅ alkyl. In yet other embodiments, Z is cyclobutyl,cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.

In some embodiments, R is hydrogen.

In some embodiments, R₁ is:

a hydrogen;

an alkoxy group optionally substituted with:

-   -   one or more halogen(s),    -   a C₆ to C₈ aryl group, or    -   a 5 or 6 membered heterocycle; or

R₁ joins together with R₂ to form:

In some embodiments, R₂ is:

-   a hydrogen;-   a halogen;-   a hydroxy group;-   a C₁ to C₆ alkyl group, optionally substituted with one or more    halogen(s);-   an amino group;-   an alkoxy group optionally substituted with:

one or more halogen(s),

an —OCOR_(x) group, where R_(x) is as defined above,

a dialkyl-amino optionally substituted with an alkoxy,

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl,

a 5 or 6 membered heteroaryl group, or

a C₆ to C₈ aryl group;

-   a —COOR_(x) group; or-   R₂ joins together with R₁ to form:

In other embodiments, at least one of R₁ and R₂ is a hydroxy group or analkoxy group optionally substituted with:

-   -   one or more halogen(s),    -   a C₆ to C₈ aryl group, or    -   a 5 or 6 membered heterocycle group; or

R₂ is a —OCOR_(x) group, a —OR_(kk) group, or an alkoxy groupsubstituted with:

-   -   an —OCOR_(x) group,    -   a dialkyl-amino optionally substituted with an alkoxy,    -   a 5 or 6 membered heterocycle group substituted with a C₁ to C₆        alkyl; or    -   a 5 or 6 membered heteroaryl group.

In yet other embodiments, R₂ is a —OR_(kk) group or an alkoxy groupoptionally substituted with:

-   -   a dialkyl-amino optionally substituted with an alkoxy,    -   a 5 or 6 membered heterocycle group optionally substituted with        a C₁ to C₆ alkyl; or    -   a 5 or 6 membered heteroaryl group.

In yet further embodiments, R₂ is a C₁ to C₆ alkoxy group optionallysubstituted with:

-   -   a 5 or 6 membered heterocycle group optionally substituted with        a C₁ to C₆ alkyl; or    -   a 5 or 6 membered heteroaryl group.

In some embodiments, R₃ is a hydrogen.

In some embodiments,

-   X is a cyano group;-   Y is a C₆ to C₈ aryl substituted with:

a —NR_(q)CONR_(q)R_(r) group,

a —NR_(t)COOR_(u) group,

a —NR_(v)SO₂R_(w) group, or

a —NHPO(OR_(x))₂ group;

-   Z is:-   a C₁ to C₆ alkyl optionally substituted with

an alkoxy, or

one or more halogen(s), or

-   a C₂ to C₆ alkylene;-   R is hydrogen;-   at least one of R₁ and R₂ is a hydroxy group or an alkoxy group    optionally substituted with:

one or more halogen(s),

a C₆ to C₈ aryl group, or

a 5 or 6 membered heterocycle group; or

-   R₂ is a —OCOR_(x) group, a —OR_(kk) group, or an alkoxy group    substituted with:

an —OCOR_(x) group,

a dialkyl-amino optionally substituted with an alkoxy,

a 5 or 6 membered heterocycle group substituted with a C₁ to C₆ alkyl;or

a 5 or 6 membered heteroaryl group; and

-   R₃ is hydrogen.

In some embodiments, Y is a phenyl substituted with a —N_(t)COOR_(u)group. In further embodiments, R_(t) is a hydrogen, and R_(u) is:

a C₁ to C₁₂ alkyl, optionally substituted with one or more groupsindependently selected from the following:

-   -   a C₆ to C₈ aryl optionally substituted with halogen,    -   an alkoxyl group optionally substituted with one or more alkoxy        groups,    -   an amino optionally substituted with one or more C₁ to C₆ alkyl,    -   halogen, or    -   a 5 or 6 membered heteroaryl,

a C₂ to C₆ alkylene,

a C₆ to C₈ aryl, optionally substituted with halogen.

-   In yet further embodiments, R_(u) is a C₁ to C₆ alkyl.

In some embodiments, Y is a phenyl substituted with a—NR_(q)CONR_(q)R_(r) group. In further embodiments, R_(q) is a hydrogenand R_(r) is:

a C₁ to C₆ alkyl optionally substituted with one or more of thefollowing:

-   -   a hydroxy,    -   an alkoxy,    -   a 5 or 6 membered heterocycle,    -   a 5 or 6 membered heteroaryl, or    -   a C₆ to C₈ aryl optionally substituted with a halogen,    -   a C₂ to C₆ alkylene group,    -   a C₁ to C₆ alkoxy group,    -   a 5 or 6 membered heterocycle group.

-   In yet further embodiments, R_(r) is a a C₁ to C₆ alkyl.

In some embodiments, Y is phenyl substituted with a —NR_(v)SO₂R_(w)group. In further embodiments, R_(v) is a hydrogen, and where R_(w) is aC₁ to C₆ alkyl.

In some embodiments, Y is phenyl substituted with a —NHPO(OR_(x))₂group.

In some embodiments,

-   Y is a phenyl substituted at the para position with:

a —NR_(q)CONR_(q)R_(r) group,

a —NR_(t)COOR_(u) group,

a —NR_(v)SO₂R_(w) group, or

a —NHPO(OR_(x))₂ group;

-   Z is a C₁ to C₆ alkyl; and-   R₂ is an alkoxy group optionally substituted with:

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl; or

a 5 or 6 membered heteroaryl group.

In some embodiments, the compound of formula I is not Compound I.

In yet another embodiment, the present invention includes compounds ofthe following:

1. A compound of formula I

-   wherein:-   X is:-   a nitro group;-   a cyano group;-   a —COR_(a) group, where R_(a) is:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or a halogen, or

a dialkyl-amino;

-   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;-   a formyl group;-   a C₆ to C₈ aryl optionally substituted with an alkoxy; or-   a 5 or 6-membered heteroaryl optionally substituted with:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or one or morehalogen(s), or

a 5 to 6 membered heteroaryl;

-   Y is:-   a haloalkyl;-   a halogen;-   a benzofuran;-   a benzothiophene;-   a dibenzofuran;-   a dibenzothiophene;-   a benzothiazole;-   a naphthalene;-   an indole, optionally substituted on the nitrogen with a C₁ to C₆    alkyl;    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined    above, or an —SO₂R_(x), where R_(x) is as defined above; or    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;-   a —NHCOR_(e) group, where R_(e) is:

a C₁ to C₆ alkyl;

a C₆ to C₈ aryl optionally substituted with:

-   -   a C₁ to C₆ alkyl,    -   an alkoxy,    -   a cyano group,    -   a nitro group, or    -   a halogen;

-   a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;

-   a —NR_(g)R_(h) group, where R_(g) is hydrogen or a C₁ to C₆ alkyl    and R_(h) is hydrogen or a C₆ to C₈ aryl optionally substituted with    an alkoxy;

-   a C₁ to C₆ alkyl;

-   a 5 or 6 membered heteroaryl, optionally substituted with:

a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,

a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where R_(x) isas defined above, or

an amino group;

-   a 5 or 6 membered heterocycle optionally substituted with:

a —COOR_(X) group, where R_(x) is as defined above, or

a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a C₆ to C₈ aryl, optionally substituted with one or more of the    following:

an alkoxy, optionally substituted with:

-   -   an alkoxy,    -   a hydroxy,    -   one or more halogen(s),    -   a 5 or 6 membered heterocycle, optionally substituted with:        -   a C₁ to C₆ alkyl, or        -   a hydroxy,    -   an amino group optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and        R_(i) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —NR_(j)COR_(k) group, where R_(k) is:        -   a C₁ to C₆ alkyl,        -   a hydrogen, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),    -   and R_(j) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —N═N⁺═N⁻ group, or    -   a —COR₁, where R₁ is a 5 or 6 membered heterocycle optionally        substituted with a hydroxy,

an amino optionally substituted with one or more C₁ to C₆ alkyl(s),

a C₁ to C₆ alkyl group, optionally substituted with:

-   -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or    -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,

a haloalkoxy,

a halogen,

a hydroxy,

a —COOR_(x) group, where R_(x) is as defined above,

a —COR_(m) group, where R_(m) is:

-   -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), where the one or more C₁ to C₆ alkyl(s) is/are        optionally substituted with:        -   a hydroxy        -   a 5 or 6 membered heterocycle,        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),        -   an alkoxy,    -   a 3 to 7 membered heterocycle, optionally substituted with a C₁        to C₆ alkyl, optionally substituted with a dialkyl-amino,    -   a —NHR_(n) group, where R_(n) is:        -   a —CH₂CONH₂, or        -   a C₆ to C₈ aryl optionally substituted with:            -   an alkyl,            -   one or more halogen(s),            -   a nitro group, or            -   one or more alkoxy(s),

a —NR_(o)COR_(p) group, where R_(p) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   an alkoxy, or        -   a C₆ to C₈ aryl,    -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with a halogen,    -   a 5 or 6 membered heteroaryl optionally substituted with one or        more C₁ to C₆ alkyl(s),    -   a hydrogen,

and where R_(o) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a haloalkyl,    -   a haloalkoxy, or    -   a —COR_(x) group, where R_(x) is as defined above,

and where R_(r) is:

-   -   a C₆ to C₈ aryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a C₁ to C₆ alkyl optionally substituted with one or more of the        following:        -   a halogen,        -   an alkylene,        -   a C₆ to C₈ aryl, and/or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a —COOR_(x) group, where R_(x) is as defined above,

a —NR_(t)COOR_(u) group, where R_(u) s:

-   -   a C₁ to C₁₂ alkyl, optionally substituted with:        -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆ alkyl            or an alkoxy,        -   an alkylene,        -   an alkoxy,        -   an alkyne,        -   a halogen, or        -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with:        -   an alkoxy,        -   a halogen, or        -   a C₁ to C₆ alkyl, or    -   a 5 or 6 membered heterocycle,

and R_(t) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(v)SO₂R_(w) group, where R_(v) is:

-   -   a hydrogen,    -   a —COR_(x), where R_(x) is as defined above, or    -   a C₁ to C₆ alkyl, optionally substituted with:        -   a halogen,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a —OCOR_(x) group, where R_(x) is as defined above,        -   a hydroxy, or        -   an alkoxy,

and where R_(w) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   a haloalkyl,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle,    -   a C₂ to C₆ alkylene,    -   an alkyl- or dialkyl-amino optionally substituted with a        halogen,    -   a 5 or 6 membered heterocycle, or    -   a 5 or 6 membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a 5 or 6 membered heterocycle, or            optionally substituted with a C₁ to C₆ alkyl, where R_(y) is            a C₁ to C₆ alkyl or hydrogen,

where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally substituted witha C₆ to C₈ aryl,

a —SR_(x) group, where R_(x) is as defined above,

a —SO₂R_(aa) group, where R_(aa) is:

-   -   a C₁ to C₆ alkyl,    -   an amino group,    -   an alkyl- or dialkyl-amino group optionally substituted with a        hydroxy or a —COOR_(x) group, where R_(x) is as defined above,    -   a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, and/or

a —NHR_(bb) group, where R_(bb) is:

-   -   a —C(═S)NH₂ group, or    -   a —PO(OR_(x))₂ group, where R_(x) is as defined above;        group, where R_(cc) is:

a naphthalene,

a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing:

-   -   an alkoxy,    -   a hydroxy,    -   a halogen,    -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,    -   a —NR_(ee)NR_(ff)R_(ff) group, where R_(ee) is a hydrogen or a        C₁ to C₆ alkyl, optionally substituted with a halogen, and        R_(ff) is:        -   a hydrogen,        -   a haloalkyl,        -   a haloalkoxy,        -   a C₁ to C₆ alkyl, or        -   a —COR_(x), where R_(x) is as defined above,    -   a —NR_(gg)COR_(hh) group, where R_(hh) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl optionally substituted with:            -   an alkoxy,            -   a halogen, or            -   an amino optionally substituted with one or more C₁ to                C₆ alkyl(s),        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s), where the one or more C₁ to C₆ alkyl(s) is/are            optionally substituted with a halogen,        -   a 5 or 6 membered heterocycle,        -   a 5 or 6 membered heteroaryl,    -   and R_(gg) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a haloalkoxy, or        -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl,    -   5 or 6 membered heterocycle groups,    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), and/or    -   a NR_(ii)SO₂R_(x) group, where R_(x) is as defined above, and        R_(ii) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a haloalkoxy,        -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:

-   a C₁ to C₆ alkyl optionally substituted with:

an alkoxy,

one or more halogen(s), or

a C₆ to C₈ aryl;

-   a C₂ to C₆ alkylene;-   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or more    C₁ to C₆ alkyl(s);-   a —COOR_(x) group, where R_(x) is as defined above; or-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:-   a hydrogen;-   a hydroxy;-   a halogen;-   a haloalkyl;-   a nitro group;-   a 5 or 6 membered heteroaryl;-   a 5 or 6 membered heterocycle;-   an alkoxy optionally substituted with:

one or more halogen(s),

a C₆ to C₈ aryl, or

a 5 or 6 membered heterocycle;

-   a C₆ to C₈ aryl optionally substituted with an alkoxy;-   a —COR_(x) group, where R_(x) is as defined above;-   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or a 5    or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:-   R₂ is:-   a nitro group;-   a hydrogen;-   a halogen;-   a hydroxy group;-   a C₁ to C₆ alkyl group, optionally substituted with one or more    halogen(s);-   an amino group;-   an alkoxy group optionally substituted with:

one or more halogen(s),

an —OCOR_(x) group, where R_(x) is as defined above,

a dialkyl-amino optionally substituted with an alkoxy,

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl,

a 5 or 6 membered heteroaryl group, or

a C₆ to C₈ aryl group;

-   a —COOR_(x) group, where R_(x) is as defined above;-   a haloalkyl;-   an amide group optionally substituted with:

a hydroxy group, or

a C₆ to C₈ aryl;

-   a 5 or 6 membered heteroaryl;-   a —OCOR_(x) group, where R_(x) is as defined above;-   a —NHCOR_(jj) group, where R_(jj) is:

an alkoxy, or

an amino optionally substituted with one or more C₁ to C₆ alkyl(s);

-   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;-   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:-   R₃ is:-   a hydrogen; or-   CH₂OCOR_(x), and R_(x) is as defined above; provided that when X is    phenyl substituted with alkoxy, Y is phenyl, R is hydrogen, R₁ is a    halogen, R₂ is hydrogen, and R₃ is hydrogen, and-   provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is    alkyl, R is hydrogen, R₁ is hydrogen or hydroxy, R₂ is hydrogen or    hydroxy, and R₃ is hydrogen, then Z is:-   a C₁ to C₆ alkyl substituted with:

an alkoxy,

one or more halogen(s), or

C₆ to C₈ aryl;

-   a C₂ to C₆ alkylene;-   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or more    C₁ to C₆ alkyl(s);-   a —COOR_(x) group, where R_(x) is as defined above; or    or a pharmaceutically acceptable salt thereof.

2. The compound of embodiment 1, wherein X is a nitro group or a cyanogroup.

3. The compound of embodiment 1, wherein X is a cyano group.

4. The compound of embodiment 1, wherein:

-   Y is a C₆ to C₈ aryl, optionally substituted with one or more of the    following:

an amino optionally substituted with one or more C₁ to C₆ alkyl(s),

a C₁ to C₆ alkyl group, optionally substituted with a —NHSO₂R_(x) group,

a —NR_(o)COR_(p) group, where R_(p) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen, or        -   a C₆ to C₈ aryl, or    -   a 5 or 6 membered heterocycle,

and where R_(o) is a hydrogen,

a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:

-   -   a hydrogen, or    -   a C₁ to C₆ alkyl,

and where R_(r) is a C₁ to C₆ alkyl optionally substituted with one ormore of the following:

-   -   a halogen,    -   an alkylene, or    -   a C₆ to C₈ aryl,

a —NR_(t)COOR_(u) group, where R_(u) is:

-   -   a C₁ to C₁₂ alkyl, optionally substituted with:        -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆ alkyl            or an alkoxy,        -   an alkylene,        -   an alkoxy,        -   an alkyne,        -   a halogen, or        -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with an alkoxy,    -   a 5 or 6 membered heterocycle,

and where R_(t) is:

-   -   a hydrogen, or    -   a C₁ to C₆ alkyl,

a —NR_(v)SO₂R_(w) group, where R_(v) is a hydrogen, and where R_(w) is aC₁ to C₆ alkyl optionally substituted with a halogen;

where R_(z) is a C₁ to C₆ alkyl, and/or

a —NHR_(bb) group, where R_(bb) is a —PO(OR_(x))₂ group.

5. The compound of embodiment 4, wherein Y is a C₆ to C₈ arylsubstituted with:

a —NR_(q)CONR_(q)R_(r) group,

a —NR_(t)COOR_(u) group,

a —NR_(v)SO₂R_(w) group, or

a —NHR_(bb) group, where R_(bb) is a —PO(OR_(x))₂ group.

6. The compound of embodiment 5, wherein the C₆ to C₈ aryl is phenyl.

7. The compound of embodiment 6, wherein the phenyl is substituted atthe para position.

8. The compound of embodiment 7, wherein Y is phenyl substituted with a—N_(q)CONR_(q)R_(r) group at the para position.

9. The compound of embodiment 7, wherein Y is phenyl substituted with a—NR_(t)COOR_(u) group at the para position.

10. The compound of embodiment 7, wherein Y is phenyl substituted with a—NR_(v)SO₂R_(w) group at the para position.

11. The compound of embodiment 7, wherein Y is phenyl substituted with a—NHPO(OR_(x))₂ group at the para position.

12. The compound of embodiment 1, wherein Z is:

-   a C₁ to C₆ alkyl optionally substituted with

an alkoxy, or

one or more halogen(s), or

-   a C₂ to C₆ alkylene.

13. The compound of embodiment 1, wherein Z is a C₁ to C₆ alkyl.

14. The compound of embodiment 13, wherein Z is a a C₂ to C₅ alkyl.

15. The compound of embodiment 14, wherein Z is cyclobutyl, cyclopropyl,cyclopropylmethyl, ethyl or cyclopentyl.

16. The compound of embodiment 1, wherein R is hydrogen.

17. The compound of embodiment 1, wherein R1 is:

a hydrogen;

an alkoxy group optionally substituted with:

-   -   one or more halogen(s),    -   a C₆ to C₈ aryl group, or    -   a 5 or 6 membered heterocycle; or

R₁ joins together with R₂ to form:

18. The compound of embodiment 1, wherein R₂ is:

-   a hydrogen;-   a halogen;-   a hydroxy group;-   a C₁ to C₆ alkyl group, optionally substituted with one or more    halogen(s);-   an amino group;-   an alkoxy group optionally substituted with:

one or more halogen(s),

an —OCOR_(x) group, where R_(x) is as defined above,

a dialkyl-amino optionally substituted with an alkoxy,

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl,

a 5 or 6 membered heteroaryl group, or

a C₆ to C₈ aryl group;

-   a —COOR_(x) group; or-   R₂ joins together with R₁ to form:

19. The compound of embodiment 1, wherein:

at least one of R₁ and R₂ is a hydroxy group or an alkoxy groupoptionally substituted with:

-   -   one or more halogen(s),    -   a C₆ to C₈ aryl group, or    -   a 5 or 6 membered heterocycle group; or

R₂ is a —OCOR_(x) group, a —OR_(kk) group, or an alkoxy groupsubstituted with:

-   -   an —OCOR_(x) group,    -   a dialkyl-amino optionally substituted with an alkoxy,    -   a 5 or 6 membered heterocycle group substituted with a C₁ to C₆        alkyl; or    -   a 5 or 6 membered heteroaryl group.

20. The compound of embodiment 19, wherein R₂ is an alkoxy groupoptionally substituted with:

-   -   a 5 or 6 membered heterocycle group optionally substituted with        a C₁ to C₆ alkyl; or    -   a 5 or 6 membered heteroaryl group.

21. The compound of embodiment 20, wherein R₂ is a C₁ to C₆ alkoxy groupoptionally substituted with:

-   -   a 5 or 6 membered heterocycle group optionally substituted with        a C₁ to C₆ alkyl; or    -   a 5 or 6 membered heteroaryl group.

22. The compound of embodiment 1, wherein R₃ is a hydrogen.

23. The compound of embodiment 1, wherein:

-   X is a cyano group;-   Y is a C₆ to C₈ aryl substituted with:

a —NR_(q)CONR_(q)R_(r) group,

a —NR_(t)COOR_(u) group,

a —NR_(v)SO₂R_(w) group, or

a —NHPO(OR_(x))₂ group;

-   Z is:-   a C₁ to C₆ alkyl optionally substituted with

an alkoxy, or

one or more halogen(s), or

-   a C₂ to C₆ alkylene;-   R is hydrogen;-   at least one of R₁ and R₂ is a hydroxy group or an alkoxy group    optionally substituted with:

one or more halogen(s),

a C₆ to C₈ aryl group, or

a 5 or 6 membered heterocycle group; or

-   R₂ is a —OCOR_(x) group, a —OR_(kk) group, or an alkoxy group    substituted with:

an —OCOR_(x) group,

a dialkyl-amino optionally substituted with an alkoxy,

a 5 or 6 membered heterocycle group substituted with a C₁ to C₆ alkyl;or

a 5 or 6 membered heteroaryl group; and

-   R₃ is hydrogen.

24. The compound of embodiment 23, wherein Y is a phenyl substitutedwith a —NR_(q)CONR_(q)R_(r) group.

25. The compound of embodiment 24, wherein:

-   Z is a C₁ to C₆ alkyl; and-   R₂ is an alkoxy group optionally substituted with:

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl; or

a 5 or 6 membered heteroaryl group.

26. The compound of embodiment 23, wherein Y is a phenyl substitutedwith a —NR_(t)COOR_(u) group.

27. The compound of embodiment 26, wherein:

-   Z is a C₁ to C₆ alkyl; and-   R₂ is an alkoxy group optionally substituted with:

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl; or

a 5 or 6 membered heteroaryl group.

28. The compound of embodiment 23, wherein Y is a phenyl substitutedwith a —NR_(v)SO₂R_(w) group.

29. The compound of embodiment 28, wherein:

-   Z is a C₁ to C₆ alkyl; and-   R₂ is an alkoxy group optionally substituted with:

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl; or

a 5 or 6 membered heteroaryl group.

30. The compound of embodiment 23, wherein Y is a —NHPO(OR_(x))₂ group.

31. The compound of embodiment 30, wherein:

-   Z is a C₁ to C₆ alkyl; and-   R₂ is an alkoxy group optionally substituted with:

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl; or

a 5 or 6 membered heteroaryl group.

32. The compound of embodiment 1, wherein:

-   X is:

a cyano group; or

a formyl group;

-   Y is:

a 5 or 6 membered heteroaryl, optionally substituted with a C₆ to C₈aryl, optionally substituted with —COOR_(x), where R_(x) is as definedabove;

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing:

-   -   a C₁ to C₆ alkyl group;    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s);    -   a halogen;    -   a hydroxy;    -   a —COR_(m) group, where R_(m) is:        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s);    -   a —N_(o)COR_(p) group, where R_(p) is:        -   a C₁ to C₆ alkyl optionally substituted with an alkoxy;    -   and where R_(o) is:        -   a hydrogen;    -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is hydrogen and where        R_(r) is:        -   a C₁ to C₆ alkyl;    -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl, optionally substituted with:            -   a C₆ to C₈ aryl;            -   a halogen; or            -   a 5 or 6 membered heterocycle;    -   a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w)        is:        -   a C₁ to C₆ alkyl; or        -   an alkyl- or dialkyl-amino;        -   where R_(z) is hydrogen or a C₁ to C₆ alkyl;    -   a —SO₂R_(aa) group, where R_(aa) is:        -   an amino group; or        -   an alkyl or dialkyl amino group;    -   a —NHR_(bb) group, where R_(bb) is:        -   a —PO(OR_(x))₂ group, where R_(x) is as defined above;

-   Z is:

a C₁ to C₆ alky; or

a —COOR_(x) group, where R_(x) is as defined above;

-   R is a hydrogen,-   R₁ is:

a hydrogen;

a 5 or 6 membered heterocycle;

an alkoxy optionally substituted with:

-   -   one or more halogen(s); or    -   a 5 or 6 membered heterocycle;

-   R₂ is:

a hydrogen;

a hydroxy group;

a C₁ to C₆ alkyl group, optionally substituted with one or morehalogen(s);

an alkoxy group optionally substituted with:

-   -   one or more halogen(s);    -   a 5 or 6 membered heterocycle group optionally substituted with        a C₁ to C₆ alkyl; or    -   a 5 or 6 membered heteroaryl group;

a —COOR_(x) group, where R_(x) is as defined above;

an amide group;

a 5 or 6 membered heteroaryl; or

a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;

-   R₃ is a hydrogen.

33. The compound of embodiment 32, wherein:

-   X is a cyano group;-   Y is:

a C₆ to C₈ aryl substituted with one or more of the following:

-   -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s);    -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is hydrogen and where        R_(r) is:        -   a C₁ to C₆ alkyl;    -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl, optionally substituted with:            -   a C₆ to C₈ aryl;    -   a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w)        is:        -   a C₁ to C₆ alkyl;

-   Z is a C₁ to C₆ alky;

-   R is a hydrogen,

-   R₁ is a hydrogen;

-   R₂ is:

an alkoxy group optionally substituted with:

-   -   one or more halogen(s);    -   a 5 or 6 membered heterocycle group optionally substituted with        a C₁ to C₆ alkyl; or    -   a 5 or 6 membered heteroaryl group; or

-   R₃ is a hydrogen.

34. The compound of embodiment 32, wherein:

-   X is a cyano group;-   Y is:

a C₆ to C₈ aryl substituted with one or more of the following:

-   -   a C₁ to C₆ alkyl group;    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s);    -   a halogen;    -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl;    -   a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w)        is:        -   a C₁ to C₆ alkyl; or        -   an alkyl- or dialkyl-amino;

-   Z is a C₁ to C₆ alky;

-   R is a hydrogen;

-   R₁ is a hydrogen;

-   R₂ is a —OR_(kk) group, where R_(kk) is a 5 to 6 membered    heteroaryl;

-   R₃ is a hydrogen.

35. The compound of embodiment 32, wherein:

-   X is:

a cyano group;

-   Y is:

a C₆ to C₈ aryl substituted with one or more of the following:

-   -   a C₁ to C₆ alkyl;    -   a halogen;    -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl;    -   a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w)        is:        -   a C₁ to C₆ alkyl; or        -   an alkyl- or dialkyl-amino; or    -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is hydrogen and where        R_(r) is:        -   a C₁ to C₆ alkyl;

-   Z is:

a C₁ to C₆ alkyl;

-   R is:

a hydrogen,

-   R₁ is:

a hydrogen;

-   R₂ is:

an alkoxy group optionally substituted with:

-   -   one or more halogen(s);

an amide;

a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl; or

a 5 or 6 membered heteroaryl;

-   R₃ is:

a hydrogen.

36. The compound of embodiment 35, wherein:

-   X is:

a cyano group;

-   Y is:

a C₆ to C₈ aryl substituted with one or more of the following:

-   -   a halogen;    -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl; or    -   a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w)        is:        -   a C₁ to C₆ alkyl;

-   Z is:

a C₁ to C₆ alkyl;

-   R is:

a hydrogen,

-   R₁ is:

a hydrogen;

-   R₂ is:

a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;

-   R₃ is:

a hydrogen.

37. The compound of embodiment 36, wherein the C₆ to C₈ aryl is phenyl.

38. The compound of embodiment 37, wherein the phenyl is substituted atthe para position.

39. The compound of embodiment 38, wherein:

-   Y is:

a phenyl substituted with a —NR_(t)COOR_(u) group, where R_(t) ishydrogen, and where R_(u) is: a C₁ to C₁₂ alkyl.

40. The compound of embodiment 38, wherein:

-   Y is:

a phenyl substituted with a halogen and a —NR_(t)COOR_(u) group, whereR_(t) is hydrogen, and where R_(u) is C₁ to C₁₂ alkyl.

41. The compound of embodiment 38, wherein:

-   Y is:

a phenyl substituted with a —NR_(v)SO₂R_(w) group, where R_(v) ishydrogen and where R_(w) is C₁ to C₆ alkyl.

42. The compound of embodiment 38, wherein:

-   Y is:

a phenyl substituted with a C₁ to C₆ alkyl and a —NR_(t)COOR_(u) group,where R_(t) is hydrogen, and where R_(u) is: a C₁ to C₁₂ alkyl.

43. The compound of embodiment 35, wherein:

-   X is:

a cyano group;

-   Y is:

a C₆ to C₈ aryl substituted with —NR_(t)COOR_(u) group, where R_(t) ishydrogen, and where R_(u) is a C₁ to C₁₂ alkyl.

-   Z is:

a C₁ to C₆ alkyl;

-   R is:

a hydrogen;

-   R₁ is:

a hydrogen;

-   R₂ is:

an alkoxy group optionally substituted with:

-   -   one or more halogen(s);

-   R₃ is:

a hydrogen.

44. The compound of embodiment 35, wherein R₂ is: an alkoxy groupsubstituted with one or more halogens.

45. The compound of embodiment 43, wherein the C₆ to C₈ aryl is phenyl.

46. The compound of embodiment 45, wherein the phenyl is substituted atthe para position.

47. The compound of embodiment 35, wherein:

-   X is:

a cyano group;

-   Y is:

a C₆ to C₈ aryl substituted with one or more of the following:

-   -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl;    -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is hydrogen and where        R_(r) is:        -   a C₁ to C₆ alkyl;

-   Z is:

a C₁ to C₆ alkyl;

-   R is:

a hydrogen,

-   R₁ is:

a hydrogen;

-   R₂ is:

a 5 or 6 membered heteroaryl;

-   R₃ is:

a hydrogen.

48. The compound of embodiment 47, wherein the C₆ to C₈ aryl is phenyl.

49. The compound of embodiment 48, wherein the phenyl is substituted atthe para position.

50. The compound of embodiment 49, wherein:

-   Y is:

a phenyl substituted with a —NR_(t)COOR_(u) group, where R_(t) ishydrogen, and where R_(u) is: a C₁ to C₁₂ alkyl.

51. The compound of embodiment 49, wherein:

-   Y is:

a C₆ to C₈ aryl substituted with a N_(q)CONR_(q)R_(r) group, where R_(q)is hydrogen and where R_(r) is a C₁ to C₆ alkyl.

52. The compound of embodiment 35, wherein:

-   X is:

a cyano group;

-   Y is:

a C₆ to C₈ aryl substituted with a —NR_(t)COOR_(u) group, where R_(t) ishydrogen, and where R_(u) is a C₁ to C₁₂ alkyl;

-   Z is:

a C₁ to C₆ alkyl;

-   R is:

a hydrogen,

-   R₁ is:

a hydrogen;

-   R₂is:

a amide;

-   R₃ is:

a hydrogen.

53. The compound of embodiment 52, wherein the C₆ to C₈ aryl is phenyl.

54. The compound of embodiment 53, wherein the phenyl is substituted atthe para position.

55. The compound of embodiment 35, wherein R₂ is: an alkoxy groupsubstituted with one or more halogen(s).

56. The compound of embodiment 35, wherein R₂ is: a —OR_(kk) group,where R_(kk) is a 5 to 6 membered heteroaryl.

57. The compound of embodiment 32, wherein

-   X is:

a formyl group;

-   Y is:

a C₆ to C₈ aryl substituted with one or more of the following:

-   -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl;    -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is hydrogen and where        R_(r) is:        -   a C₁ to C₆ alkyl;

-   Z is:

a C₁ to C₆ alky;

-   R is:

a hydrogen;

-   R₁ is:

a hydrogen;

R₂ is:

an alkoxy group;

-   R₃ is:

a hydrogen.

58. The compound of embodiment 32, wherein:

-   X is:

a cyano group;

-   Y is:

a C₆ to C₈ aryl substituted with one or more of the following:

-   -   a C₁ to C₆ alkyl group;    -   a halogen;    -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl, optionally substituted with:            -   a C₆ to C₈ aryl;    -   a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w)        is:        -   a C₁ to C₆ alkyl; or        -   an alkyl- or dialkyl-amino;

-   Z is:

a C₁ to C₆ alky;

-   R is:

a hydrogen;

-   R₁ is:

a hydrogen;

-   R₂ is:

an alkoxy group substituted with one or more halogen(s);

-   R₃is:

a hydrogen.

59. The compound of embodiment 32, wherein:

-   X is:

a cyano group;

-   Y is:

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing:

-   -   a —NR_(o)COR_(p) group, where R_(p) is:        -   a C₁ to C₆ alkyl optionally substituted with an alkoxy;    -   and where R_(o) is:        -   a hydrogen;

-   Z is:    -   a C₁ to C₆ alky;

-   R is:

a hydrogen;

-   R₁ is:

a hydrogen;

-   R₂ is:

an alkoxy group substituted with a 5 or 6 membered heteroaryl group;

-   R₃ is:

a hydrogen.

60. The compound of embodiment 32, wherein:

-   X is:

a cyano group;

-   Y is:

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing:

-   -   a C₁ to C₆ alkyl group;    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s);    -   a halogen;    -   a —NR_(o)COR_(p) group, where R_(p) is:        -   a C₁ to C₆ alkyl;    -   and where R_(o) is:        -   a hydrogen;    -   a —NR_(q)CON_(q)R_(r) group, where R_(q) is hydrogen and where        R_(r) is:        -   a C₁ to C₆ alkyl;    -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl;    -   a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w)        is:        -   a C₁ to C₆ alkyl;    -   a —NHR_(bb) group, where R_(bb) is:        -   a —PO(OR_(x))₂ group, where R_(x) is as defined above;

-   Z is:

a C₁ to C₆ alky;

-   R is:

a hydrogen,

-   R₁ is:

a hydrogen;

-   R₂ is:

a 5 or 6 membered heteroaryl;

-   R₃ is:

a hydrogen.

61. The compound of embodiment 32, wherein:

-   X is:

a cyano group;

-   Y is:

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing:

-   -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s);    -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is hydrogen and where        R_(r) is:        -   a C₁ to C₆ alkyl;    -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl, optionally substituted with:            -   a C₆ to C₈ aryl; or            -   a 5 or 6 membered heterocycle;    -   a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w)        is:        -   a C₁ to C₆ alkyl;        -   where R_(z) is hydrogen or a C₁ to C₆ alkyl;

-   Z is:

a C₁ to C₆ alky;

-   R is:

a hydrogen,

-   R₁ is:

a 5 or 6 membered heterocycle;

an alkoxy substituted with:

-   -   one or more halogen(s); or    -   a 5 or 6 membered heterocycle;

-   R₂ is:

a hydrogen;

-   R₃ is:

a hydrogen.

62. The compound of embodiment 61, wherein R₁ is a 5 or 6 memberedheterocycle.

63. The compound of embodiment 61, wherein R₁ is an alkoxy substitutedwith one or more halogen.

64. The compound of embodiment 61, wherein:

-   Y is:

a C₆ to C₈ aryl substituted with:

-   -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl, optionally substituted with:            -   a C₆ to C₈ aryl; or            -   a 5 or 6 membered heterocycle;

-   R₁ is:

an alkoxy substituted with one or more halogen.

65. A compound of formula IIIa

-   wherein:-   X is:

hydrogen;

-   Y is:

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing:

-   -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is hydrogen and where        R_(r) is:        -   a C₁ to C₆ alkyl;    -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl;    -   a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w)        is:        -   a C₁ to C₆ alkyl;

-   Z is:

a C₁ to C₆ alky;

-   R is:

a hydrogen,

-   R₁ is:

a hydrogen;

-   R₂ is:

an alkoxy group optionally substituted with:

-   -   one or more halogen(s); or

a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;

-   R₃ is:

a hydrogen.

66. The compound of embodiment 65, wherein:

-   X is:

hydrogen;

-   Y is:

a C₆ to C₈ aryl substituted with a —NR_(t)COOR_(u) group, where R_(t) ishydrogen, and where R_(u) is a C₁ to C₁₂ alkyl;

-   Z is:

a C₁ to C₆ alkyl;

-   R is:

a hydrogen,

-   R₁ is:

a hydrogen;

-   R₂ is:

a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;

-   R₃ is:

a hydrogen.

67. The compound of embodiment 65, wherein the C₆ to C₈ aryl is phenyl.

68. The compound of embodiment 65, wherein the phenyl is substituted atthe para position.

69. A pharmaceutical composition comprising:

(i) a compound of formula I

-   wherein:-   X is:-   a nitro group;-   a cyano group;-   a —COR_(a) group, where R_(a) is:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or a halogen, or

a dialkyl-amino;

-   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;-   a formyl group;-   a C₆ to C₈ aryl optionally substituted with an alkoxy; or-   a 5 or 6-membered heteroaryl optionally substituted with:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or one or morehalogen(s), or

a 5 to 6 membered heteroaryl;

-   Y is:-   a haloalkyl;-   a halogen;-   an amino optionally substituted with one or more C₁ to C₆ alkyl(s);-   a benzofuran;-   a benzothiophene;-   a dibenzofuran;-   a dibenzothiophene;-   a benzothiazole;-   a naphthalene;-   an indole, optionally substituted on the nitrogen with a C₁ to C₆    alkyl;    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined    above, or an —SO₂R_(x), where R_(x) is as defined above; or    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;-   a —NHCOR_(e) group, where R_(e) is:

a C₁ to C₆ alkyl;

a C₆ to C₈ aryl optionally substituted with:

-   -   a C₁ to C₆ alkyl,    -   an alkoxy,    -   a cyano group,    -   a nitro group, or    -   a halogen;

-   a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;

-   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a hydrogen    and R_(h) is a C₆ to C₈ aryl optionally substituted with an alkoxy;

-   a C₁ to C₆ alkyl;

-   a 5 or 6 membered heteroaryl, optionally substituted with:

a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,

a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where R_(x) isas defined above, or

an amino group;

-   a 5 or 6 membered heterocycle optionally substituted with:

a —COOR_(x) group, where R_(x) is as defined above, or

a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a C₆ to C₈ aryl, optionally substituted with one or more of the    following:

an alkoxy, optionally substituted with:

-   -   an alkoxy,    -   a hydroxy,    -   one or more halogen(s),    -   a 5 or 6 membered heterocycle, optionally substituted with:        -   a C₁ to C₆ alkyl, or        -   a hydroxy,    -   an amino group optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and        R_(i) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —NR_(j)COR_(k) group, where R_(k) is:        -   a C₁ to C₆ alkyl,        -   a hydrogen, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),    -   and R_(j) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —N═N⁺═N⁻ group, or    -   a —COR₁, where R₁ is a 5 or 6 membered heterocycle optionally        substituted with a hydroxy,

an amino optionally substituted with one or more C₁ to C₆ alkyl(s),

a nitro group,

a C₁ to C₆ alkyl group, optionally substituted with:

-   -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or    -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,

a haloalkoxy,

a halogen,

a hydroxy,

a —COOR_(x) group, where R_(x) is as defined above,

a —COR_(m) group, where R_(m) is:

-   -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), where the C₁ to C₆ alkyls are optionally substituted        with:        -   a hydroxy        -   a 5 or 6 membered heterocycle,        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),        -   an alkoxy,    -   a 3 to 7 membered heterocycle, optionally substituted with a C₁        to C₆ alkyl, optionally substituted with a dialkyl-amino,    -   a —NHR_(n) group, where R_(n) is:    -   a —CH₂CONH₂, or        -   a C₆ to C₈ aryl optionally substituted with:            -   an alkyl,            -   one or more halogen(s),            -   a nitro group, or            -   one or more alkoxy(s),

a —NR_(o)COR_(p) group, where R_(p) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   an alkoxy, or        -   a C₆ to C₈ aryl,    -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with a halogen,    -   a 5 or 6 membered heteroaryl optionally substituted with one or        more C₁ to C₆ alkyl(s),    -   a hydrogen,

and where R_(o) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a haloalkyl,    -   a haloalkoxy, or    -   a —COR_(x) group, where R_(x) is as defined above,

and where R_(r) is:

-   -   a C₆ to C₈ aryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a C₁ to C₆ alkyl optionally substituted with one or more of the        following:        -   a halogen,        -   an alkylene,        -   a C₆ to C₈ aryl, and/or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a —COOR_(x) group, where R_(x) is as defined above,

a —NR_(t)COOR_(u) group, where R_(u) is:

-   -   a C₁ to C₁₂ alkyl, optionally substituted with:        -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆ alkyl            or an alkoxy,        -   an alkylene,        -   an alkoxy,        -   an alkyne,        -   a halogen, or        -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with:        -   an alkoxy,        -   a halogen, or        -   a C₁ to C₆ alkyl, or    -   a 5 or 6 membered heterocycle,

and R_(t) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(v)SO₂R_(w) group, where R_(v) is:

-   -   a hydrogen,    -   a —COR_(x), where R_(x) is as defined above, or    -   a C₁ to C₆ alkyl, optionally substituted with:        -   a halogen,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a —OCOR_(x) group, where R_(x) is as defined above,        -   a hydroxy, or        -   an alkoxy,

and where R_(w) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   a haloalkyl,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle,    -   a C₂ to C₆ alkylene,    -   an alkyl- or dialkyl-amino optionally substituted with a        halogen,    -   a 5 or 6 membered heterocycle, or    -   a 5 or 6 membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a 5 or 6 membered heterocycle, or            optionally substituted with a C₁ to C₆ alkyl, where R_(y) is            a C₁ to C₆ alkyl or hydrogen,

where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally substituted witha C₆ to C₈ aryl,

a —SR_(x) group, where R_(x) is as defined above,

a —SO₂R_(aa) group, where R_(aa) is:

-   -   a C₁ to C₆ alkyl,    -   an amino group,    -   an alkyl- or dialkyl-amino group optionally substituted with a        hydroxy or a —COOR_(x) group, where R_(x) is as defined above,    -   a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, and/or

a —NHR_(bb) group, where R_(bb) is:

-   -   a —C(═S)NH₂ group, or    -   a —PO(OR_(x))₂ group, where R_(x) is as defined above;        group, where R_(cc) is:

a naphthalene,

a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing:

-   -   an alkoxy,    -   a hydroxy,    -   a halogen,    -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,    -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen or a        C₁ to C₆ alkyl, optionally substituted with a halogen, and        R_(ff) is:        -   a hydrogen,        -   a haloalkyl,        -   a haloalkoxy,        -   a C₁ to C₆ alkyl, or        -   a —COR_(x), where R_(x) is as defined above,    -   a —NR_(gg)COR_(hh) group, where R_(hh) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl optionally substituted with:            -   an alkoxy,            -   a halogen, or            -   an amino optionally substituted with one or more C₁ to                C₆ alkyl(s),        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s), where the alkyls are optionally substituted with a            halogen,        -   a 5 or 6 membered heterocycle,        -   a 5 or 6 membered heteroaryl,    -   and R_(gg) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a haloalkoxy, or        -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl,    -   5 or 6 membered heterocycle groups,    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), and/or    -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above, and        R_(ii) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a haloalkoxy,        -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:

-   a C₁ to C₆ alkyl optionally substituted with:

an alkoxy,

one or more halogen(s), or

a C₆ to C₈ aryl;

-   a C₂ to C₆ alkylene;-   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or more    C₁ to C₆ alkyl(s);-   a —COOR_(x) group, where R_(x) is as defined above; or-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:-   a hydrogen;-   a hydroxy;-   a halogen;-   a haloalkyl;-   a nitro group;-   a 5 or 6 membered heteroaryl;-   a 5 or 6 membered heterocycle;-   an alkoxy optionally substituted with:

one or more halogen(s),

a C₆ to C₈ aryl, or

a 5 or 6 membered heterocycle;

-   a C₆ to C₈ aryl optionally substituted with an alkoxy;-   a —COR_(x) group, where R_(x) is as defined above;-   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or a 5    or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:-   R₂ is:-   a nitro group;-   a hydrogen;-   a halogen;-   a hydroxy group;-   a C₁ to C₆ alkyl group, optionally substituted with one or more    halogen(s);-   an amino group;-   an alkoxy group optionally substituted with:

one or more halogen(s),

an —OCOR_(x) group, where R_(x) is as defined above,

a dialkyl-amino optionally substituted with an alkoxy,

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl,

a 5 or 6 membered heteroaryl group, or

a C₆ to C₈ aryl group;

-   a —COOR_(x) group, where R_(x) is as defined above;-   a haloalkyl;-   an amide group optionally substituted with:

a hydroxy group, or

a C₆ to C₈ aryl;

-   a 5 or 6 membered heteroaryl;-   a —OCOR_(x) group, where R_(x) is as defined above;-   a —NHCOR_(jj) group, where R_(jj) is:

an alkoxy, or

an amino optionally substituted with one or more C₁ to C₆ alkyl(s);

-   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;-   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:-   R₃ is:-   a hydrogen; or-   —CH₂OCOR_(x), and R_(x) is as defined above;-   provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is    alkyl, R is hydrogen, R₁ is hydrogen or hydroxy, R₂ is hydrogen or    hydroxy, and R₃ is hydrogen,-   then Z is:-   a C₁ to C₆ alkyl substituted with:

an alkoxy,

one or more halogen(s), or

a C₆ to C₈ aryl;

-   a C₂ to C₆ alkylene;-   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or more    C₁ to C₆ alkyl(s);-   a —COOR_(x) group, where R_(x) is as defined above; or

or one or more pharmaceutically acceptable salt(s) thereof; and

(ii) one or more pharmaceutically acceptable excipient(s).

70. A method for treating an infection by a virus in a subject in needthereof, wherein the virus contains an internal ribosome entry site(IRES), comprising administering to the subject one or more compound(s)of formula I or a pharmaceutical composition comprising one or morecompound(s) of formula I

-   wherein:-   X is:-   a nitro group;-   a cyano group;-   a —COR_(a) group, where R_(a) is:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or a halogen, or

a dialkyl-amino;

-   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;-   a formyl group;-   a C₆ to C₈ aryl optionally substituted with an alkoxy; or-   a 5 or 6-membered heteroaryl optionally substituted with:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or one or morehalogen(s), or

a 5 to 6 membered heteroaryl;

-   Y is:-   a haloalkyl;-   a halogen;-   an amino optionally substituted with one or more C₁ to C₆ alkyl(s);-   a benzofuran;-   a benzothiophene;-   a dibenzofuran;-   a dibenzothiophene;-   a benzothiazole;-   a naphthalene;-   an indole, optionally substituted on the nitrogen with a C₁ to C₆    alkyl;    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined    above, or an —SO₂R_(x), where R_(x) is as defined above; or    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;-   a —NHCOR_(e) group, where R_(e) is:

a C₁ to C₆ alkyl;

a C₆ to C₈ aryl optionally substituted with:

-   -   a C₁ to C₆ alkyl,    -   an alkoxy,    -   a cyano group,    -   a nitro group, or    -   a halogen;

-   a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;

-   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a hydrogen    and R_(h) is a C₆ to C₈ aryl optionally substituted with an alkoxy;

-   a C₁ to C₆ alkyl;

-   a 5 or 6 membered heteroaryl, optionally substituted with:

a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,

a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where R_(x) isas defined above, or

an amino group;

-   a 5 or 6 membered heterocycle optionally substituted with:

a —COOR_(x) group, where R_(x) is as defined above, or

a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a C₆ to C₈ aryl, optionally substituted with one or more of the    following:

an alkoxy, optionally substituted with:

-   -   an alkoxy,    -   a hydroxy,    -   one or more halogen(s),    -   a 5 or 6 membered heterocycle, optionally substituted with:        -   a C₁ to C₆ alkyl, or        -   a hydroxy,    -   an amino group optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and        R_(i) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —NR_(j)COR_(k) group, where R_(k) is:        -   a C₁ to C₆ alkyl,        -   a hydrogen, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),    -   and R_(j) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —N═N⁺═N⁻ group, or    -   a —COR₁, where R₁ is a 5 or 6 membered heterocycle optionally        substituted with a hydroxy,

an amino optionally substituted with one or more C₁ to C₆ alkyl(s),

a nitro group,

a C₁ to C₆ alkyl group, optionally substituted with:

-   -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or    -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,

a haloalkoxy,

a halogen,

a hydroxy,

a —COOR_(x) group, where R_(x) is as defined above,

a —COR_(m) group, where R_(m) is:

-   -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), where the one or more C₁ to C₆ alkyl(s) is/are        optionally substituted with:        -   a hydroxy        -   a 5 or 6 membered heterocycle,        -   an amino optionally substituted with one or more C₁ to C₆            alkyls, and/or        -   an alkoxy,    -   a 3 to 7 membered heterocycle, optionally substituted with a C₁        to C₆ alkyl, optionally substituted with a dialkyl-amino,    -   a —NHR_(n) group, where R_(n) is:        -   a —CH₂CONH₂, or        -   a C₆ to C₈ aryl optionally substituted with:            -   an alkyl,            -   one or more halogen(s),            -   a nitro group, or            -   one or more alkoxy(s),

a —NR_(o)COR_(p) group, where R_(p) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   an alkoxy, or        -   a C₆ to C₈ aryl,    -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with a halogen,    -   a 5 or 6 membered heteroaryl optionally substituted with one or        more C₁ to C₆ alkyl(s),    -   a hydrogen,

and where R_(o) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a haloalkyl,    -   a haloalkoxy, or    -   a —COR_(x) group, where R_(x) is as defined above,

and where R_(r) is:

-   -   a C₆ to C₈ aryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a C₁ to C₆ alkyl optionally substituted with one or more of the        following:        -   a halogen,        -   an alkylene,        -   a C₆ to C₈ aryl, and/or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a —COOR_(x) group, where R_(x) is as defined above,

a —NR_(t)COOR_(u) group, where R_(u) is:

-   -   a C₁ to C₁₂ alkyl, optionally substituted with:        -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆ alkyl            or an alkoxy,        -   an alkylene,        -   an alkoxy,        -   an alkyne,        -   a halogen, or        -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with:        -   an alkoxy,        -   a halogen, or        -   a C₁ to C₆ alkyl, or    -   a 5 or 6 membered heterocycle,

and R_(t) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(v)SO₂R_(w) group, where R_(v) is:

-   -   a hydrogen,    -   a —COR_(x), where R_(x) is as defined above, or    -   a C₁ to C₆ alkyl, optionally substituted with:        -   a halogen,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a —OCOR_(x) group, where R_(x) is as defined above,        -   a hydroxy, or        -   an alkoxy,

and where R_(w) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   a haloalkyl,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle,    -   a C₂ to C₆ alkylene,    -   an alkyl- or dialkyl-amino optionally substituted with a        halogen,    -   a 5 or 6 membered heterocycle, or    -   a 5 or 6 membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a 5 or 6 membered heterocycle, or            optionally substituted with a C₁ to C₆ alkyl, where R_(y) is            a C₁ to C₆ alkyl or hydrogen,

where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally substituted witha C₆ to C₈ aryl,

a —SR_(x) group, where R_(x) is as defined above,

a —SO₂R_(aa) group, where R_(aa) is:

-   -   a C₁ to C₆ alkyl,    -   an amino group,    -   an alkyl- or dialkyl-amino group optionally substituted with a        hydroxy or a —COOR_(x) group, where R_(x) is as defined above,    -   a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, and/or

a —NHR_(bb) group, where R_(bb) is:

-   -   a —C(═S)NH₂ group, or    -   a —PO(OR_(x))₂ group, where R_(x) is as defined above;        group, where R_(cc) is:

a naphthalene,

a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing:

-   -   an alkoxy,    -   a hydroxy,    -   a halogen,    -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,    -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen or a        C₁ to C₆ alkyl, optionally substituted with a halogen, and        R_(ff) is:        -   a hydrogen,        -   a haloalkyl,        -   a haloalkoxy,        -   a C₁ to C₆ alkyl, or        -   a —COR_(x), where R_(x) is as defined above,    -   a —NR_(gg)COR_(hh) group, where R_(hh) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl optionally substituted with:            -   an alkoxy,            -   a halogen, or            -   an amino optionally substituted with one or more C₁ to                C₆ alkyl(s),        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),        -   where the alkyls are optionally substituted with a halogen,        -   a 5 or 6 membered heterocycle,        -   a 5 or 6 membered heteroaryl,    -   and R_(gg) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a haloalkoxy, or        -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl,    -   5 or 6 membered heterocycle groups,    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), and/or    -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above, and        R_(ii) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a haloalkoxy,        -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:

-   a C₁ to C₆ alkyl optionally substituted with:

an alkoxy,

one or more halogen(s), or

a C₆ to C₈ aryl;

-   a C₂ to C₆ alkylene;-   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or more    C₁ to C₆ alkyl(s);-   a —COOR_(x) group, where R_(x) is as defined above; or-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:-   a hydrogen;-   a hydroxy;-   a halogen;-   a haloalkyl;-   a nitro group;-   a 5 or 6 membered heteroaryl;-   a 5 or 6 membered heterocycle;-   an alkoxy optionally substituted with:

one or more halogen(s),

a C₆ to C₈ aryl, or

a 5 or 6 membered heterocycle;

-   a C₆ to C₈ aryl optionally substituted with an alkoxy;-   a —COR_(x) group, where R_(x) is as defined above;-   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or a 5    or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:-   R₂ is:-   a nitro group;-   a hydrogen;-   a halogen;-   a hydroxy group;-   a C₁ to C₆ alkyl group, optionally substituted with one or more    halogen(s);-   an amino group;-   an alkoxy group optionally substituted with:

one or more halogen(s),

an —OCOR_(x) group, where R_(x) is as defined above,

a dialkyl-amino optionally substituted with an alkoxy,

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl,

a 5 or 6 membered heteroaryl group, or

a C₆ to C₈ aryl group;

-   a —COOR_(x) group, where R_(x) is as defined above;-   a haloalkyl;-   an amide group optionally substituted with:

a hydroxy group, or

a C₆ to C₈ aryl;

-   a 5 or 6 membered heteroaryl;-   a —OCOR_(x) group, where R_(x) is as defined above;-   a —NHCOR_(jj) group, where R_(jj) is:

an alkoxy, or

an amino optionally substituted with one or more C₁ to C₆ alkyl(s);

-   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;-   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:-   R₃ is:-   a hydrogen; or-   CH₂OCOR_(x), and R_(x) is as defined above; or-   one or more pharmaceutically acceptable salt(s) thereof.

71. A method for treating a Hepatitis C viral (HCV) infection in asubject in need thereof, comprising administering to the subject one ormore compound(s) of formula I or a pharmaceutical composition comprisingone or more compound(s) of formula I

-   wherein:-   X is:-   a nitro group;-   a cyano group;-   a —COR_(a) group, where R_(a) is:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or a halogen, or

a dialkyl-amino;

-   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;-   a formyl group;-   a C₆ to C₈ aryl optionally substituted with an alkoxy; or-   a 5 or 6-membered heteroaryl optionally substituted with:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or one or morehalogen(s), or

a 5 to 6 membered heteroaryl;

-   Y is:-   a haloalkyl;-   a halogen;-   an amino optionally substituted with one or more C₁ to C₆ alkyl(s);-   a benzofuran;-   a benzothiophene;-   a dibenzofuran;-   a dibenzothiophene;-   a benzothiazole;-   a naphthalene;-   an indole, optionally substituted on the nitrogen with a C₁ to C₆    alkyl;    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined    above, or an —SO₂R_(x), where R_(x) is as defined above; or    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;-   a —NHCOR_(e) group, where R_(e) is:

a C₁ to C₆ alkyl;

a C₆ to C₈ aryl optionally substituted with:

-   -   a C₁ to C₆ alkyl,    -   an alkoxy,    -   a cyano group,    -   a nitro group, or    -   a halogen;

-   a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;

-   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a hydrogen    and R_(h) is a C₆ to C₈ aryl optionally substituted with an alkoxy;

-   a C₁ to C₆ alkyl;

-   a 5 or 6 membered heteroaryl, optionally substituted with:

a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,

a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where R_(x) isas defined above, or

an amino group;

-   a 5 or 6 membered heterocycle optionally substituted with:

a —COOR_(x) group, where R_(x) is as defined above, or

a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a C₆ to C₈ aryl, optionally substituted with one or more of the    following:

an alkoxy, optionally substituted with:

-   -   an alkoxy,    -   a hydroxy,    -   one or more halogen(s),    -   a 5 or 6 membered heterocycle, optionally substituted with:        -   a C₁ to C₆ alkyl, or        -   a hydroxy,    -   an amino group optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and        R_(i) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —NR_(j)COR_(k) group, where R_(k) is:        -   a C₁ to C₆ alkyl,        -   a hydrogen, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),    -   and R_(j) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —N═N⁺═N⁻ group, or    -   a —COR₁, where R₁ is a 5 or 6 membered heterocycle optionally        substituted with a hydroxy,

an amino optionally substituted with one or more C₁ to C₆ alkyl(s),

a nitro group,

a C₁ to C₆ alkyl group, optionally substituted with:

-   -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or    -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,

a haloalkoxy,

a halogen,

a hydroxy,

a —COOR_(x) group, where R_(x) is as defined above,

a —COR_(m) group, where R_(m) is:

-   -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), where the one or more C₁ to C₆ alkyl(s) is/are        optionally substituted with:        -   a hydroxy        -   a 5 or 6 membered heterocycle,        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),        -   an alkoxy,    -   a 3 to 7 membered heterocycle, optionally substituted with a C₁        to C₆ alkyl,    -   optionally substituted with a dialkyl-amino,    -   a —NHR_(n) group, where R_(n) is:        -   a —CH₂CONH₂, or        -   a C₆ to C₈ aryl optionally substituted with:            -   an alkyl,            -   one or more halogen(s),            -   a nitro group, or            -   one or more alkoxy(s),

a —NR_(o)COR_(p) group, where R_(p) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   an alkoxy, or        -   a C₆ to C₈ aryl,    -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with a halogen,    -   a 5 or 6 membered heteroaryl optionally substituted with one or        more C₁ to C₆ alkyl(s),    -   a hydrogen,

and where R_(o) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(q)CON_(q)R_(r) group, where R_(q) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a haloalkyl,    -   a haloalkoxy, or    -   a —COR_(x) group, where R_(x) is as defined above,

and where R_(r) is:

-   -   a C₆ to C₈ aryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a C₁ to C₆ alkyl optionally substituted with one or more of the        following:        -   a halogen,        -   an alkylene,        -   a C₆ to C₈ aryl, and/or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a —COOR_(x) group, where R_(x) is as defined above,

a —NR_(t)COOR_(u) group, where R_(u) is:

-   -   a C₁ to C₁₂ alkyl, optionally substituted with:        -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆ alkyl            or an alkoxy,        -   an alkylene,        -   an alkoxy,        -   an alkyne,        -   a halogen, or        -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with:        -   an alkoxy,        -   a halogen, or        -   a C₁ to C₆ alkyl, or    -   a 5 or 6 membered heterocycle,

and R_(t) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(v)SO₂R_(w) group, where R_(v) is:

-   -   a hydrogen,    -   a —COR_(x), where R_(x) is as defined above, or    -   a C₁ to C₆ alkyl, optionally substituted with:        -   a halogen,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a —OCOR_(x) group, where R_(x) is as defined above,        -   a hydroxy, or        -   an alkoxy,

and where R_(w) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   a haloalkyl,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle,    -   a C₂ to C₆ alkylene,    -   an alkyl- or dialkyl-amino optionally substituted with a        halogen,    -   a 5 or 6 membered heterocycle, or    -   a 5 or 6 membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a 5 or 6 membered heterocycle, or            optionally substituted with a C₁ to C₆ alkyl, where R_(y) is            a C₁ to C₆ alkyl or hydrogen,

where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally substituted witha C₆ to C₈ aryl,

a —SR_(x) group, where R_(x) is as defined above,

a —SO₂R_(aa) group, where R_(aa) is:

-   -   a C₁ to C₆ alkyl,    -   an amino group,    -   an alkyl- or dialkyl-amino group optionally substituted with a        hydroxy or a —COOR_(x) group, where R_(x) is as defined above,    -   a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, and/or

a —NHR_(bb) group, where R_(bb) is:

-   -   a —C(═S)NH₂ group, or    -   a —PO(OR_(x))₂ group, where R_(x) is as defined above;        group, where R_(cc) is:

a naphthalene,

a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing:

-   -   an alkoxy,    -   a hydroxy,    -   a halogen,    -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,    -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen or a        C₁ to C₆ alkyl, optionally substituted with a halogen, and        R_(ff) is:        -   a hydrogen,        -   a haloalkyl,        -   a haloalkoxy,        -   a C₁ to C₆ alkyl, or        -   a —COR_(x), where R_(x) is as defined above,    -   a —NR_(gg)COR_(hh) group, where R_(hh) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl optionally substituted with:            -   an alkoxy,            -   a halogen, or            -   an amino optionally substituted with one or more C₁ to                C₆ alkyl(s),        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),        -   where the one or more C₁ to C₆ alkyl(s) is/are optionally            substituted with a halogen,        -   a 5 or 6 membered heterocycle,        -   a 5 or 6 membered heteroaryl,    -   and R_(gg) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a haloalkoxy, or        -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl,    -   5 or 6 membered heterocycle groups,    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), and/or    -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above, and        R_(ii) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a haloalkoxy,        -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:

-   a C₁ to C₆ alkyl optionally substituted with:

an alkoxy,

one or more halogen(s), or

a C₆ to C₈ aryl;

-   a C₂ to C₆ alkylene;-   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or more    C₁ to C₆ alkyl(s);-   a —COOR_(x) group, where R_(x) is as defined above; or-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:-   a hydrogen;-   a hydroxy;-   a halogen;-   a haloalkyl;-   a nitro group;-   a 5 or 6 membered heteroaryl;-   a 5 or 6 membered heterocycle;-   an alkoxy optionally substituted with:

one or more halogen(s),

a C₆ to C₈ aryl, or

a 5 or 6 membered heterocycle;

-   a C₆ to C₈ aryl optionally substituted with an alkoxy;-   a —COR_(x) group, where R_(x) is as defined above;-   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or a 5    or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:-   R₂is:-   a nitro group;-   a hydrogen;-   a halogen;-   a hydroxy group;-   a C₁ to C₆ alkyl group, optionally substituted with one or more    halogen(s);-   an amino group;-   an alkoxy group optionally substituted with:

one or more halogen(s),

an —OCOR_(x) group, where R_(x) is as defined above,

a dialkyl-amino optionally substituted with an alkoxy,

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl,

a 5 or 6 membered heteroaryl group, or

a C₆ to C₈ aryl group;

-   a —COOR_(x) group, where R_(x) is as defined above;-   a haloalkyl;-   an amide group optionally substituted with:

a hydroxy group, or

a C₆ to C₈ aryl;

-   a 5 or 6 membered heteroaryl;-   a —OCOR_(x) group, where R_(x) is as defined above;-   a —NHCOR_(jj) group, where R_(jj) is:

an alkoxy, or

an amino optionally substituted with one or more C₁ to C₆ alkyl(s);

-   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;-   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:-   R₃ is:-   a hydrogen; or-   —CH₂OCOR_(x), and R_(x) is as defined above; or-   one or more pharmaceutically acceptable salt(s) thereof.

72. A compound of formula IIIb

-   wherein:-   X is:

hydrogen;

-   Y is:

a 5 or 6 membered heteroaryl, optionally substituted with a C₆ to C₈aryl, optionally substituted with —COOR_(x), where R_(x) is as definedabove;

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing:

-   -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s);    -   a halogen;    -   a hydroxy;    -   a —COR_(m) group, where R_(m) is:        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s);    -   a —NR_(o)COR_(p) group, where R_(p) is:        -   a C₁ to C₆ alkyl optionally substituted with an alkoxy;    -   and where R_(o) is:        -   a hydrogen;    -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is hydrogen and where        R_(r) is:        -   a C₁ to C₆ alkyl;    -   a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where        R_(u) is:        -   a C₁ to C₁₂ alkyl, optionally substituted with:            -   a C₆ to C₈ aryl;            -   a halogen; or            -   a 5 or 6 membered heterocycle;    -   a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w)        is:        -   a C₁ to C₆ alkyl; or        -   an alkyl- or dialkyl-amino;        -   where R_(z) is hydrogen or a C₁ to C₆ alkyl;    -   a —SO₂R_(aa) group, where R_(aa) is:        -   an amino group; or        -   an alkyl- or dialkyl-amino group;    -   a —NHR_(bb) group, where R_(bb) is:        -   a —PO(OR_(x))₂ group, where R_(x) is as defined above;

-   Z is:

a C₁ to C₆ alky; or

a —COOR_(x) group, where R_(x) is as defined above;

-   R is:

a hydrogen,

-   R₁ is:

a hydrogen;

a 5 or 6 membered heterocycle;

an alkoxy optionally substituted with:

-   -   one or more halogen(s); or    -   5 or 6 membered heterocycle;

-   R₂is:

a hydrogen;

a hydroxy group;

a C₁ to C₆ alkyl group, optionally substituted with one or morehalogen(s);

an alkoxy group optionally substituted with:

-   -   one or more halogen(s);    -   a 5 or 6 membered heterocycle group optionally substituted with        a C₁ to C₆ alkyl;    -   a 5 or 6 membered heteroaryl group; or

a —COOR_(x) group, where R_(x) is as defined above;

an amide group;

a 5 or 6 membered heteroaryl; or

a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;

-   R₃ is:

a hydrogen.

73. The compound of embodiment 72, wherein:

-   X is:

hydrogen;

-   Y is:

a C₆ to C₈ aryl, substituted with —NR_(t)COOR_(u) group, where R_(t) ishydrogen, and where R_(u) is a C₁ to C₁₂ alkyl;

-   Z is:

a C₁ to C₆ alky;

-   R is:

a hydrogen;

-   R₁ is:

a hydrogen;

-   R₂ is:

a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;

-   R₃ is:

a hydrogen

74. A compound which is selected from the compound range: 866-1329,1484-2127, 2129-2545.

75. The compound of embodiment 74 selected from:

As used herein, the term “alkyl” generally refers to saturatedhydrocarbyl radicals of straight, branched or cyclic configuration, orcombinations of cyclic and branched or straight, including methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, n-hexyl, cyclohexyl, n-heptyl, octyl, n-octyl, and the like.In some embodiments, alkyl substitutes may be C₁ to C₁₂, or C₁ to C₈ orC₁ to C₆ alkyl groups.

As used herein, “alkylene” generally refers to linear, branched orcyclic alkene radicals having one or more carbon-carbon double bonds,such as C₂ to C₆ alkylene groups including 3-propenyl.

As used herein, “aryl” refers to a carbocyclic aromatic ring structure.Included in the scope of aryl groups are aromatic rings having from fiveto twenty carbon atoms. Aryl ring structures include compounds havingone or more ring structures, such as mono-, bi-, or tricyclic compounds.Examples of aryl groups that include phenyl, tolyl, anthracenyl,fluorenyl, indenyl, azulenyl, phenanthrenyl (i.e., phenanthrene), andnapthyl (i.e., napthalene) ring structures. In certain embodiments, thearyl group may be optionally substituted.

As used herein, “heteroaryl” refers to cyclic aromatic ring structuresin which one or more atoms in the ring, the heteroatom(s), is an elementother than carbon. Heteroatoms are typically O, S or N atoms. Includedwithin the scope of heteroaryl, and independently selectable, are O, N,and S heteroaryl ring structures. The ring structure may includecompounds having one or more ring structures, such as mono-, bi-, ortricyclic compounds. In some embodiments, the heteroaryl groups may beselected from heteroaryl groups that contain two or more heteroatoms,three or more heteroatoms, or four or more heteroatoms. Heteroaryl ringstructures may be selected from those that contain five or more atoms,six or more atoms, or eight or more atoms. Examples of heteroaryl ringstructures include: acridine, benzimidazole, benzoxazole, benzodioxole,benzofuran, 1,3-diazine, 1,2-diazine, 1,2-diazole, 1,4-diazanaphthalene,furan, furazan, imidazole, indole, isoxazole, isoquinoline, isothiazole,oxazole, purine, pyridazine, pyrazole, pyridine, pyrazine, pyrimidine,pyrrole, quinoline, quinoxaline, thiazole, thiophene, 1,3,5-triazine,1,2,4-triazine, 1,2,3-triazine, tetrazole and quinazoline.

As used herein, “heterocycle” refers to cyclic ring structures in whichone or more atoms in the ring, the heteroatom(s), is an element otherthan carbon. Heteroatoms are typically O, S or N atoms. Included withinthe scope of heterocycle, and independently selectable, are O, N, and Sheterocycle ring structures. The ring structure may include compoundshaving one or more ring structures, such as mono-, bi-, or tricycliccompounds. Example of heterocyclo groups include morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl,tetrahydrothiophenyl or tetrahydrothiopyranyl and the like. In certainembodiments, the heterocycle may optionally be substituted.

As used herein, “alkoxy” generally refers to a group with the structure—O—R, where R is an alkyl group as defined above.

For the purposes of this invention, halo substitutes may beindependently selected from the halogens such as fluorine, chlorine,bromine, iodine, and astatine. A haloalkyl is an alkyl group, as definedabove, substituted with one or more halogens. A haloalkoxy is an alkoxygroup, as defined above, substituted with one or more halogens.

For the purposes of this invention, where one or more functionalitiesencompassing X, Y, Z, R, R₁, R₂, and R₃, are incorporated into amolecule of formula I, each functionality appearing at any locationwithin the disclosed compound may be independently selected, and asappropriate, independently substituted. Further, where a more genericsubstituent is set forth for any position in the molecules of thepresent invention, it is understood that the generic substituent may bereplaced with more specific substitutes, and the resulting molecules arewithin the scope of the molecules of the present invention.

By “substituted” or “optionally substituted” it is meant that theparticular substituent may be substituted with a chemical group known toone of skill in the art to be appropriate for the referred-tosubstituent, unless a chemical group is specifically mentioned.

In some embodiments, X is selected from the X substitutes of compounds866-1329, 1484-2127, 2129-2545.

Nonlimiting examples of X substituents include the following, wherethe * indicates the bond of attachment of the scaffold molecule:

In some embodiments, the X substituent is hydrogen; a cyano group; or a—COR_(a) group, where R_(a) is a C₁ to C₆ alkyl, or a dialkyl-amino.

In other embodiments, the X substituent is selected from the following:

In yet other embodiments, the X substituent is selected from thefollowing:

In some embodiments, Y is selected from the Y substituents of compounds866-1329, 1484-2127, 2129-2545.

Nonlimiting examples of Y substituents include the following:

In some embodiments, the Y substituent is selected from the following:

In other embodiments, the Y substituent is selected from the following:

In some embodiments, Z is selected from the Z substituents of compounds866-1329, 1484-2127, 2129-2545.

Nonlimiting examples of Z substituents include the following:

In some embodiments, the Z substituent is a hydrogen; a C₁ to C₆ alkyloptionally substituted with an alkoxy, one or more halogens, or a C₆ toC₈ aryl; a C₂ to C₆ alkylene; or a C₆ to C₈ aryl optionally substitutedwith an alkoxy.

In other embodiments, the Z substituent is selected from the following:

In yet other embodiments, the Z substituent is a hydrogen; a C₁ to C₆alkyl optionally substituted with: a C₆ to C₈ aryl; a C₂ to C₆ alkylene;and a C₆ to C₈ aryl optionally substituted with an alkoxy.

In yet further embodiments, the Z substituent is selected from thefollowing:

In some embodiments, R is selected from the R substituents of compounds866-1329, 1484-2127, 2129-2545.

Nonlimiting examples of R substituents include the following:

In some embodiments, the R substituent is the following:

In some embodiments, R₁ is selected from the R₁ substituents ofcompounds 866-1329, 1484-2127, 2129-2545.

Nonlimiting examples of R₁ substituents include the following:

The R₁ substituent is a hydrogen; a halogen; a nitro group; a 5 or 6membered heterocycle; an alkoxy optionally substituted with a C₆ to C₈aryl; or a C₆ to C₈ aryl optionally substituted with an alkoxy.

In other embodiments, the R₁ substituent is selected from the following:

In yet other embodiments, the R₁ substituent is selected from thefollowing:

In some embodiments, R₂ is selected from the R₂ substituents ofcompounds 866-1329, 1484-2127, 2129-2545.

Nonlimiting examples of R₂ substituents include the following:

In some embodiments, the R₂ substituent is a nitro group; a hydrogen; ahalogen; a hydroxy group; a C₁ to C₆ alkyl group, optionally substitutedwith one or more halogen(s); an alkoxy group optionally substituted withone or more halogen(s), a —OCOR_(x) group, where R_(x) is as definedabove, a dialkyl-amino optionally substituted with an alkoxy, a 5 or 6membered heterocycle group optionally substituted with a C₁ to C₆ alkyl,or a 5 or 6 membered heteroaryl group; an amide group; or a —NHSO₂R_(x)group, where R_(x) is as defined above.

In other embodiments, the R₂ substituent is selected from the following:

In yet other embodiments, the R₂ substituent is a hydrogen; a C₁ to C₆alkyl group, optionally substituted with one or more halogens; or analkoxy group optionally substituted with one or more halogens, a 5 or 6membered heterocycle group optionally substituted with a C₁ to C₆ alkyl,or a 5 or 6 membered heteroaryl group.

In yet further embodiments, the R₂ substituent is selected from thefollowing:

In some embodiments, R₃ is selected from the R₃ substituents ofcompounds 866-1329, 1484-2127, 2129-2545.

Nonlimiting examples of R₃ substituents include the following:

In some embodiments, the R₃ substituent is the following:

Nonlimiting examples of compounds of formula I include the following:

In some embodiments, the compound is selected from Compounds 866-1329,1484-2127, 2129-2545.

B. PREPARATION OF COMPOUNDS OF THE INVENTION

The compounds of the invention can be obtained via standard, well-knownsynthetic methodology. Many of the indole starting materials can beprepared using the routes described below or by those skilled in theart.

Compounds of formula I, represented by structure II can be prepared bythe methodology depicted in Scheme A below:

An α-nitroketone derivative A2 can be derived from treatment of theanion of nitromethane, obtained from the treatment of nitromethane witha base, such as, e.g., sodium or potassium t-butoxide or sodium hydride,with an activated carboxylic acid derivative, e.g., the acyl imidazolideA1. Reaction of the a-nitroketone A2 with amine derivative A3 can affordthe nitro enamine A4 by mixing the components A3 and A4 and heating in asuitable solvent such as an alcohol or an aprotic solvent. Treatment ofthe nitro enamine A4 with quinone A5 in a polar protic solvent such asacetic acid at or near ambient temperature gives the compound of formulaII.

Compounds of formula I, represented by structure III can be prepared asshown in Scheme B below:

Treatment of B1 with a reactive alkyl or aryl group containing a leavinggroup L in a suitable solvent, with or without heat in the presence of abase, such an inorganic base, e.g., sodium or potassium carbonate or anorganic base, e.g., triethylamine, can afford the compound of structureIII. Examples of leaving groups include but are not limited to halogens(e.g., chlorine, bromine or iodine) or alkyl or arylsulfonates.

Compounds of formula I, represented by structure IV can be prepared asshown in Scheme C below:

Compounds of structure IV can be obtained by nitrating an indole ofstructure C1, to give the 3-nitroindole C2. The nitration can be carriedout by treatment of C1 with a nitrating agent, such as nitric acid orsodium nitrite in a solvent such as acetic acid, acetic anhydride,sulfuric acid or in a mixed solvent system containing an organic solventsuch as dichloromethane. The reaction can be carried out a temperatureof −30° C. to +50° C. Treatment of C2 with a reactive functional groupR₉ containing a suitable leaving group L (C3) can give compounds ofstructure IV. Reactive functional groups can consist of but are notlimited to alkyl and aralkyl. L can represent a halide, particularlychloro, bromo or iodo or an alkylsulfonate. The reaction between C2 andC3 can be carried out in a suitable solvent in the presence of aninorganic base such as potassium carbonate or sodium hydride or anorganic base such as a trialkylamine. Alternatively, the group R₉ canrepresent an aryl or heteroaryl group and L can represent a halide,particularly chloro, bromo or iodo. The reaction can be carried out in apolar or nonpolar solvent at a temperature from ambient to 200° C. inthe presence of a copper catalyst, e.g., CuI, a base such as Cs₂CO₃ orK₃PO₄, and optionally an amine ligand such as 1,2-bis(methylamino)ethaneor 1,2-cyclohexanediamine.

An alternative pathway is to convert C1 into C4 in similar fashion asdescribed above and then carry out the nitration reaction to affordcompounds of structure IV.

Compounds of formula I, represented by structure V can be prepared asshown in Scheme D.

Treatment of β-ketoesters of structure D1 with amines D2 gives the aminocrotonate derivatives D3 by heating in a suitable solvent such as analcohol or an aprotic solvent. Reaction between D3 and quinone D4 in apolar protic solvent, such as acetic acid gives compounds of structureV.

Compounds of the present invention, represented by structure VIcompounds can be prepared by the chemistry described in scheme E below.

Indole-3-carboxylic esters E1 can be converted to indole-3-carboxylicacids E2 by treatment of compounds of structure E1 with, for example,either acid or base in aqueous or mixed aqueous-organic solvents atambient or elevated temperature or by treatment with nucleophilicagents, for example, boron tribromide or trimethylsilyl iodide, in asuitable solvent. Compounds of type E2 can then be activated and treatedwith amines of type E3 to give compounds E4. Activation of thecarboxylic acid can be carried out, for example, by any of the standardmethods. For example, the acid E2 can be activated with couplingreagents such as EDCI or DCC with or without HOBt in the presence of theamine E3, or alternatively the acid can be activated as the acidchloride by treatment of the acid with, e.g., thionyl chloride or oxalylchloride or as the acyl imidazolide, obtained by treatment of the acidwith carbonyl diimidazole, followed by treatment of the amine E3.Compounds E4 can be converted to compounds of structure VI by treatmentof E4 with a reactive functional group R₉ containing a suitable leavinggroup L (E5) as described previously. Alternatively, compounds of typeE1 can be converted to compounds of structure E6 by treatment with E5.Indole-3-carboxylic esters E6 can then be converted toindole-3-carboxylic acids E7 by the methods described above. Conversionof E7 to compounds of structure VI can be carried out by the activationand reaction with an amine E3 as described above.

Compounds of the present invention, represented by structure VIIcompounds can be prepared by the chemistry described in scheme F below.

Indoles F1 can be formylated with reagents such as phosphorousoxychloride in the presence of DMF to give the indole-3-carboxaldehydesF2. Conversion to compounds of structure VII can be accomplished bytreatment of F2 with compounds F3 as described previously.Alternatively, compounds of type F1 can first be converted to F4 andthen be formylated to compounds of structure VII.

Compounds of formula G, represented by structure VIII can be prepared asshown in Scheme G.

Indole-3-carboxaldehydes of structure G1 can be converted to theindole-3-carboxylic acid derivatives by oxidation with reagents such aspotassium permanganate under aqueous conditions.

Compounds of formula H, represented by structure IX can be prepared asshown in Scheme H.

Indole-3-carboxaldehydes of structure H1 can be converted to theindole-3-carbonitrile derivatives H2 by a variety of methods. Treatmentof H1 with a nitroalkane, e.g., nitropropane, in the presence of anamine source, e.g., ammonium hydrogen phosphate gives theindole-3-carbonitrile H2 derivative. An alternative pathway to compoundH2 is via the intermediate H3. Conversion of Hi to the oxime derivativeH3 can be followed by dehydration, e.g., treatment of the oxime withacetic anhydride and a base, or reaction of the oxime with thionylchloride to give H2. The compound H2 can then be reacted with a reactivefunctional group R₉ containing a suitable leaving group L (H4) asdescribed previously to afford compounds of structure IX.

Alternatively, H1 can be reacted with a reactive functional group R₉containing a suitable leaving group L (H4) to give the intermediate H5,which can be reacted with a nitroalkane as above to give theindole-3-carbonitrile IX compound. Compound IX can also be obtained byconversion to the oxime H6 followed by a dehydration reaction asdescribed above.

Compounds of the present invention, represented by structure X can alsobe prepared as described in scheme I below.

Indoles I1 can be cyanated with an appropriate cyanating agent, e.g.,chlorosulfonyl isocyanate (I2) or a dialkyl phosphoryl isocyanate in asuitable solvent or solvent mixture, e.g. DMF, CH₃CN or dioxane, toafford compounds of structure I3. The compound I3 can then be reactedwith a reactive functional group R₉ containing a suitable leaving groupL (I4) as described previously afford the compound X.

Alternatively, compound II can be reacted with a reactive functionalgroup R₉ containing a suitable leaving group L to give compounds ofstructure I5 that can then be cyanated as above to give compounds offormula X.

Compounds of formula J, represented by structure XI can be prepared asshown in Scheme J.

Amino crotonates J1 can be reacted with amines J2 to give J3. Reactionof J3 with quinone in the presence of a polar, protic solvent, e.g.,acetic acid, gives the compound of structure XI.

Compounds of the present invention, represented by structure XII andXIII can be prepared as described in scheme K below.

Aldehydes of structure K1 can be reacted with an alkyl azidoacetate K2by heating the components together in a suitable organic solvent, e.g.,a protic or non-protic solvent, in the presence of an organic orinorganic base, to give the α-azidoacrylate K3. Heating K3 in thepresence of a suitable non-reactive organic solvent, e.g., toluene orxylenes can give the 2-alkoxycarbonylindoles K4. Reduction of the esterfunctionality with a suitable reducing reagent, for example, lithiumaluminum hydride, in a suitable solvent, e.g., ether or THF can give theintermediate K5. Reaction of K5 with a reactive functional group R₉containing a suitable leaving group L (K6) as described previouslyaffords the compound K7. Cyanation of K7 with a cyanating agent, e.g.,chlorosulfonyl isocyanate as described previously can give compound XII.Alternatively, cyanation of K5 with chlorosulfonyl isocyanate gives K8,which can be reacted with a reactive functional group R₉ containing asuitable leaving group L (K6) as described previously, affords, thecompound XII.

An alternative use of intermediate K4 is exemplified below. Hydrolysisof the 2-alkoxycarbonyl group of the indole K4 either under acidic orbasic conditions followed by decarboxylation can give the intermediateK9. Decarboxylation can be carried out thermally, i.e., heating in anappropriate solvent, e.g., toluene, xylenes, or quinoline.Alternatively, a source of copper can be added, for example, copperbronze, to facilitate decarboxylation. Reaction of K9 with a reactivefunctional group R₉ containing a suitable leaving group L (K6) asdescribed above can afford the compounds K10. Cyanation of K10 with acyanating agent, e.g., chlorosulfonyl isocyanate as described previouslycan give compound XIII. Alternatively, cyanation of K9 withchlorosulfonyl isocyanate gives K11, which can be reacted with areactive functional group R₉ containing a suitable leaving group L (K6)as described previously, affords the compound XIII.

Compounds of formula L, represented by structure XIV can be prepared asshown in Scheme L.

Compounds of formula L1 can be halogenated on the 2-methyl group to give2-bromomethyl or chloromethyl indoles L2. The halogenation reaction canbe conducted with reagents, e.g., N-bromo- or chlorosuccinimide. Thereaction can be conducted in a suitable solvent, such as chloroform,carbon tetrachloride, or THF and carried out in a range between ambienttemperature and 80° C. Optionally, a radical initiator may be added,e.g., benzoyl peroxide or AIBN. The compound L2 can then be reacted witha nucleophile R₅—W (L3) to give compounds of structure XIV. The reactioncan be conducted in a suitable solvent, e.g., THF, CH₂Cl₂ or DMF, withina temperature range of 0° C. to 120° C. A base, e.g., an inorganic base,such as potassium carbonate or an organic base, such as a trialkylaminecan be used to remove the acid formed in the reaction. The group W canrefer to an N, O or S atom.

Compounds of the present invention, represented by structure XV can beprepared as described in scheme M below.

Anilines of structure M1 can be diazotized and the resulting diazoniumsalt can be reduced to give the phenyl hydrazine compound M2. Reactionbetween the hydrazine M2 and a ketone M3 under acidic conditions cangive the indole compound M4. The conditions for the cyclization reactioncan be carried out under typical conditions utilized by one skilled inthe art, for example, acidic conditions, utilizing acids such as aBronstead acid, e.g., acetic acid, hydrochloric acid or polyphosphoricacid or a Lewis acid, e.g., zinc chloride. The reaction can be carriedout in the presence of a co-solvent, e.g., CH₂Cl₂ or THF typicallywithin a temperature range of 0° C. to 120° C. Reaction of M4 with areactive functional group R₉ containing a suitable leaving group L (M5)as described previously, can afford compounds M6. Cyanation of theindole M6 with a cyanating agent such as chlorosulfonyl isocyanate cangive the compound of structure XV.

Alternatively, the indoles M4 can be cyanated to give compounds ofstructure M7. Reaction of M7 with a reactive functional group R₉containing a suitable leaving group L (M5) as described above can givecompounds of structure XV.

Compounds of formula I, represented by structure XVI can be prepared asshown in Scheme N.

Compounds of formula N1 can be reacted with a dialkylformamide dialkylacetal, N2, e.g., dimethylformamide dimethyl acetal, optionally in thepresence of a suitable solvent, e.g., DMF or dioxane, at a temperaturerange from ambient to 150° C. to give the compound of structure N3.Reduction of the nitro group of compounds of type N3 under standardconditions can give the indole compounds of structure N4. The reductioncan be carried out via hydrogenation, using a sub-stoichiometric amountof a hydrogenation catalyst, e.g., platinum or palladium, in thepresence of a hydrogen source in a protic or aprotic solvent. Thereduction can be carried out in a temperature range of ambient to 80° C.Alternatively, the reduction can be carried out via chemical reduction,e.g., in the presence of stoichiometric amounts of Fe or Sn compounds ina suitable solvent at a temperature range of ambient to 100° C. Thecompound N4 can then be reacted with a reactive functional group R₉containing a suitable leaving group L (N5) as described previously toafford compounds of structure N6. Cyanation of N6 with a cyanating agentsuch as chlorosulfonyl isocyanate in a suitable solvent can give thecompounds of structure XVI.

Alternatively, compounds of structure N4 can be cyanated to givecompounds of structure N7. Reaction of N7 with a reactive functionalgroup R₉ containing a suitable leaving group L (N5) as described abovecan give compounds of structure XVI.

Compounds of formula I, represented by structure XVII can be prepared asshown in Scheme O.

Compounds of structure O1 can be converted to 2-iodo- or bromoindolesO2. Typically, a strong base, such as n-butyllithium or s-butyllithiumor lithium diisopropylamide or lithium or potassium hexamethyldisilazideis employed, with formation of the 2-indolyl anion generated in asuitable unreactive solvent, e.g., ether or THF, or solvent mixturescontaining them. The reaction is typically carried out in the range of−78° C. to ambient temperature. The 2-indolyl anion can then be quenchedwith an electrophilic source of halogen, including but not limited toiodine, bromine or N-bromosuccinimide to give compounds of structure O2.Reaction of 2-iodo- or bromoindoles O2 with a boronic acid (commonlyreferred to as a Suzuki reaction) or trialkyl stannane (commonlyreferred to as a Stille reaction) can give the compounds of structureXVII. The coupling reactions are carried out by methods known to thoseskilled in the art and include conducting the reaction in the presenceof a catalyst, such as tetrakis(triphenylphosphine)palladium (0),bis(triphenylphosphine)palladium (II) dichloride or palladium acetatewith added phosphine ligand. The reactions are carried out in a suitablesolvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at atemperature range of ambient to 150° C. For the Suzuki reaction, a baseis usually added. The base can be in aqueous solution, e.g., aqueoussodium carbonate or sodium bicarbonate, or the base can be employedunder anhydrous conditions, e.g., cesium or potassium fluoride. For theStille reaction a copper co-catalyst, e.g., copper iodide, can be added.

Alternatively, indoles O1 can be converted to the indole-2-boronic acidor indole-2-trialkylstannane derivatives O3 by reacting the 2-indolylanion described above with a trialkylborate or chlorotrialkyl stannanederivative, respectively. Compounds of type O3 can be reacted with aryland heteroaryl bromides and iodides under similar conditions to thosedescribed above to form compounds of structure XVII.

Compounds of formula I, represented by structure XVIII can be preparedas shown in Scheme P.

Compounds of structure P1 can be converted to compounds P3 by treatmentof P1 with an aryl or heteroaryl halide (P2) in the presence oforganometallic catalysis. Such catalyst combinations can includepalladium catalysts, e.g., palladium acetate and a source of copper,e.g., copper iodide. The reaction can be carried out in the presence ofa base, e.g., cesium carbonate. The reaction can be carried out within atemperature range of ambient temperature to 150° C. Cyanation of theindole P3 with a cyanating agent such as chlorosulfonyl isocyanate cangive the compound of structure XVIII.

Compounds of the present invention, represented by structure XIX can beprepared as described in scheme Q below.

Compounds of structure XIX can be prepared by protecting an indolecompound of structure Q1 as e.g., the N-Boc derivative Q2.Alternatively, other protecting groups that can be utilized but notlimited to include, e.g., benzyl, alkyl or aryl sulfonyl, or trialkylsilyl. Treatment of Q2 with a strong base, e.g., lithium diisopropylamide in an aprotic solvent, e.g., THF followed by quenching with atrialkylborate derivative can give the indolyl-2-boronic acid Q3.Reaction with an aryl or heteroaryl halide Q4 in the presence ofpalladium catalysis, e.g., tetrakis(triphenylphosphine)palladium (0),bis(triphenylphosphine)palladium (II) dichloride or palladium acetatewith added phosphine ligand, can give the compound Q5. Removal of theprotecting group can give Q6. Reaction with Q6 with a reactivefunctional group R₉ containing a suitable leaving group L as describedabove can give compounds of structure Q7. Cyanation of compound Q7 cangive the compounds of structure XIX.

Compounds of formula I, represented by structure XX can be prepared asshown in Scheme R.

Compounds of structure R2 can be prepared by protecting an indolecompound of structure R1 as e.g., the N-Boc derivative R2 as above.Compounds of structure R2 can be converted to 2-iodo- or bromoindolesR3. Typically, a strong base, such as n-butyllithium or s-butyllithiumor lithium diisopropylamide or lithium or potassium hexamethyldisilazideis employed, with formation of the 2-indolyl anion generated in asuitable unreactive solvent, e.g., ether or THF, or solvent mixturescontaining them. The reaction is typically carried out in the range of−78° C. to ambient temperature. The 2-indolyl anion can then be quenchedwith an electrophilic source of halogen, including but not limited toiodine, bromine or N-bromosuccinimide to give compounds of structure R3.After removal of the protecting group, compounds of R4 can be reactedwith aryl or heteroaryl boronic acids or esters (R5) (commonly referredto as a Suzuki reaction) to give compounds of structure R6. The couplingreactions are carried out by methods known to those skilled in the artand include conducting the reaction in the presence of a catalyst, suchas tetrakis(triphenylphosphine)palladium (0),bis(triphenylphosphine)palladium (II) dichloride or palladium acetatewith added phosphine ligand. Reaction of R6 with a reactive functionalgroup R₉ containing a suitable leaving group L as described above cangive compounds of structure XX.

Compounds of the present invention, represented by structure XXI can beprepared as described in scheme S below.

2-iodo- or bromoindoles of structure S1 can be reacted with alkenes inthe presence of a palladium catalyst (commonly referred to as the Heckreaction) to give compounds of type XXI. The coupling reactions can becarried out by methods known to those skilled in the art. The choice ofcatalyst and solvents are similar to those described previously.

Compounds of formula I, represented by structure XXII can be prepared asshown in Scheme T.

2-Iodo- or 2-bromoindoles of structure T1 can be reacted with acetylenesin the presence of a palladium catalyst (commonly referred to as theSonagashira reaction) to give compounds of type XXII. The couplingreactions can be carried out by methods known to those skilled in theart. A typical set of reaction conditions includes reacting the indolesof structure T1 with an acetylene compound T2 in the presence of asource of palladium, a copper co-catalyst and an amine source. Thereaction is carried out in a suitably unreactive solvent and conductedwithin a temperature range from ambient to 150° C.

Compounds of formula I, represented by structure XXIII can be preparedas shown in Scheme U.

Compounds of structure XXIII can be obtained from the reduction ofcompounds XXI and XXII. Conditions for the reduction can include, butare not limited to catalytic reduction, e.g., hydrogenation over asource of platinum or palladium in a suitable solvent, e.g., CH₂Cl₂,ether, THF, methanol or solvent combinations.

Compounds of the present invention, represented by structure XXIV can beprepared as described in scheme V below.

Indoles of structure VI can be reacted with a suitable base, such aslithium diisopropylamide or potassium hexamethyldisilazide to generatethe 2-indolyl anion in a suitable unreactive solvent, e.g., ether orTHF, or solvent mixtures containing them. The reaction is typicallycarried out in the range of −78° C. to ambient temperature. The2-indolyl anion can then be quenched with a source of zinc halide, e.g.,zinc halide metal or solutions containing them to give organozinccompounds of structure V2. Reaction of V2 with an arylhalide (V3) in thepresence of a palladium catalyst (commonly referred to as the Negishireaction) gives compounds of structure XXIV. Alternatively, 2-iodo orbromoindoles of structure V4, prepared from compounds V1 as describedpreviously, can be reacted with organozinc compounds of structure V5 inthe presence of a suitable palladium catalyst to give compounds ofstructure XXIV. The organozinc compound V5 can be derived from, e.g., analkyl or alkenyl halide after treatment with activated zinc or an arylor heteroaryl lithium or magnesium compound after treatment with zinchalide. Furthermore, the reactions of V2 or V4 can be carried out in thepresence of a palladium source, e.g., astetrakis(triphenylphosphine)palladium (0) orbis(triphenylphosphine)palladium (II) dichloride in a suitable solventand at a temperature range from ambient to 150° C.

Compounds of formula I, represented by structure XXV-XXVIII can beprepared as shown in Scheme W.

2-Iodo- or bromoindoles of structure W1 can be reacted with acetylenesof structure W2 in the presence of a palladium catalyst (commonlyreferred to as the Sonagashira reaction) to give compounds of type XXV.The coupling reactions can be carried out by methods known to thoseskilled in the art. A typical set of reaction conditions includesreacting the indoles of structure W1 with an acetylene compound W2 inthe presence of a source of palladium, an optional copper co-catalystand an amine source. The reaction is carried out in a suitablyunreactive solvent and conducted within a temperature range from ambientto 150° C. Reaction with XXV with a reactive functional group R₉containing a suitable leaving group L as described above can givecompounds of structure XXVI.

2-iodo- or bromoindoles of structure W1 can also be reacted with alkenesin the presence of a palladium catalyst (commonly referred to as theHeck reaction) to give compounds of type XXVII. The coupling reactionscan be carried out by methods known to those skilled in the art. Thechoice of catalyst and solvents are similar to those describedpreviously. Reaction with XXVII with a reactive functional group R₉containing a suitable leaving group L as described above can givecompounds of structure XXVIII.

Compounds of formula I, represented by structure XXIX can be prepared asshown in Scheme X.

Indoles of structure X1 and be acylated with acyl halides of structureX2 to give compounds of structure XXIX. The reaction can be promotedwith a Lewis acid. The choice of Lewis acid can be chosen from, but isnot limited to aluminum chloride, ferric chloride, stannic chloride ordiethyl aluminum. The reaction is typically carried out in a suitablenon-reactive solvent including CH₂Cl₂, carbon disulfide ordichloroethane and is typically conducted within a temperature range of−20° C. to 80° C.

Compounds of formula I, represented by structure XXX can be prepared asshown in Scheme Y.

3-Cyanoindoles of structure Y1 can be converted to tetrazoles ofstructure Y2 by treatment with, e.g., sodium azide. Heating a mixture ofY2 and the reagent Y3 can give the 3-(1,2,4-oxadiazolyl)indole compoundXXX. The reagent Y3 can be, e.g., an acyl halide or an acid derivativeactivated with a reagent such as dicyclohexyl carbodiimide ordiisopropyl carbodiimide. The reaction can be carried out in a varietyof solvents, including e.g., toluene, dioxane, pyridine anddichloroethane and can be carried out by heating Y2 and Y3 at atemperature range of 300 to 130° C.

Compounds of formula I, represented by structure XXXI can be prepared asshown in Scheme Z.

3-Cyanoindoles of structure Z1 can be treated with hydroxyamine to givehydroxyamidine compounds of formula Z2. Reaction of hydroxyamidines ofstructure Z2 with compounds of structure Z3 can giveO-acylhydroxyamidines Z4. Compounds Z3 can represent, for example, acylhalides or carboxylic acids activated with a reagent such asdicyclohexyl carbodiimide or diisopropyl carbodiimide. Heating compoundsof structure Z4 in a non-reactive organic solvent, e.g., toluene,dichloroethane or dioxane in a temperature range of 30° C. to 150° C.can give compounds of structure XXXI.

Compounds of the present invention, represented by structure XXXII canbe prepared as described in scheme AA below.

Ketoindoles of type AA1 can be converted to oximes of structure AA2 byheating the ketoindoles with hydroxyamine (free base or acid salt) in asuitable solvent. Bis-deprotonation of compounds of type AA2 with astrong organic base (e.g., n-butyllityium or sec-butyllithium ortert-butyllithium) followed by reaction with DMF can give compounds offormula XXXII.

Compounds of formula I, represented by structure XXXIII can be preparedas shown in Scheme AB.

3-Ketoindoles of structure AB1 can be homologated to vinylogous amidesof structure AB3 by reaction with dialkyl amide dialkyl acetals AB2. Thedialkyl amides can include e.g., lower alkyl amides such as formamide,acetamide and propionamide. Examples would include dimethlformamidedimethyl acetal and dimethyl acetamide dimethyl acetal. The reaction canbe conducted by reacting AB1 and AB2 with or without additional solventat a temperature from ambient to 150° C. Treatment of AB3 withhydroxyamine (free base or acid salt) in a suitable solvent can givecompounds of structure XXXIII. The reaction is typically conductedwithin a temperature range from ambient to 120° C.

Compounds of formula I, represented by structure XXXIV can be preparedas shown in Scheme AC.

Vinylogous amides of structure AC1 (as prepared above) can be treatedwith hydrazines AC2 in a suitable organic solvent (DMF, alcohol oracetic acid) at temperatures ranging from ambient temperature to 150° C.to give compounds of structure XXXIV.

Compounds of the present invention, represented by structure XXXV can beprepared as described in scheme AD below.

Indole-3-carboxaldehydes of structure AD1 (as prepared in Scheme F) canbe reacted with p-(toluenesulfonyl)methyl isocyanate (TOSMIC) in thepresence of a base to give compounds of structure XXXV. Bases caninclude potassium carbonate or 1,8-diazabicyclo[5.4.0]undec-7-ene andthe reaction can be carried out in a suitable organic solvent fromambient temperature to 150° C.

Compounds of formula I, represented by structures XXXVI and XXXVII canbe prepared as shown in Scheme AE.

3-Indolecarboxylic acids of structure AE1 (from Scheme E) can beconverted to amides of structure AE2. Compounds of structure AE2 can beactivated by any of the standard methods. For example, the acid AE1 canbe activated with coupling reagents such as EDCI or DCC with or withoutHOBt in the presence of ammonia. Alternatively, the acid can beactivated as the acid chloride or as the acyl imidazolide as describedpreviously, followed by treatment of ammonia.

The indole-3-carboxamides of structure AE2 can be reacted withsubstituted aldehydes or ketones (AE3) containing a suitable leavinggroup L, in a suitable solvent at temperatures above ambient and up to200° C. The reaction can be performed with or without added base toafford oxazoles of structure XXXVI.

The indole-3-carboxamides of structure AE2 can also be converted tothioamides of structure AE4 by treating the primary amides withLawesson's reagent or phosphorous pentasulfide at or above ambienttemperature in a suitable organic solvent. The resulting thioamides AE4can be reacted with substituted aldehydes or ketones containing asuitable leaving group L (AE3), in a suitable solvent at temperaturesabove ambient and up to 150° C. The reaction can be performed with orwithout added base to afford thiazoles of structure XXXVII.

Compounds of the present invention, represented by structure XXXVIII andXXXIX can be prepared as described in scheme AF below.

3-Ketoindoles of structure AF1 can be halogenated (e.g., brominated) togive compounds of structure AF3. Suitable brominating agents can includebut are not limited to phenyltrimethylammonium tribromide (AF2),N-bromosuccinimide or bromine and can be carried out in a variety oforganic solvents.

Treatment of compounds AF3 with amides of type AF4 in a suitable solventat temperatures above ambient and up to 200° C. with or without addedbase can give oxazoles of structure XXXVIII.

Treatment of compounds AF3 with thioamides of type AF5 in a suitablesolvent at temperatures above ambient and up to 150° C. with or withoutadded base can give thiazoles of structure XXXIX.

Compounds of formula I, represented by structure XL can be prepared asshown in Scheme AG.

Indoles of structure AG1 can be brominated or iodinated to givecompounds of structure AG2. Brominating agents may include but are notlimited to bromine or N-bromosuccinimide and iodinating reagents mayinclude iodine monochloride or bis-trifluoroacetoxy iodobenzene.Reaction of 3-iodo- or bromoindoles AG2 with a boronic acid AG3(commonly referred to as a Suzuki reaction) can give the compounds ofstructure XL. The coupling reactions are carried out by methods known tothose skilled in the art and include conducting the reaction in thepresence of a catalyst, such as tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium (II) dichloride or palladiumacetate with added phosphine ligand. The reactions are carried out in asuitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at atemperature range of ambient to 150° C. and typically in the presence ofa base e.g., aqueous sodium carbonate or sodium bicarbonate, or the basecan be employed under anhydrous conditions, e.g., cesium or potassiumfluoride.

Alternatively, indole AG2 can be converted to the indole-3-boronic acidderivative AG5 by reacting the 3-haloindole AG2 with a strong organicbase (alkyllithium or Grignard reagent) and reacting the resultant anionwith a trialkylborate reagent AG4. Compounds of type AG5 can be reactedwith aryl and heteroaryl bromides and iodides under similar conditionsto those described above to form compounds of structure XL.

Compounds of the present invention, represented by structure XLI can beprepared as described in scheme AH below.

3-iodo- or bromoindoles of structure AH1 can be reacted with alkenes AH2in the presence of a palladium catalyst (commonly referred to as theHeck reaction) to give compounds of type XLI. The coupling reactions canbe carried out by methods known to those skilled in the art. The choiceof catalyst and solvents are similar to those described in Scheme AG.

Compounds of formula I, represented by structure XLII can be prepared asshown in Scheme AI.

3-Iodo- or bromoindoles of structure AI1 can be reacted with acetylenesAI2 in the presence of a palladium catalyst (commonly referred to as theSonagashira reaction) to give compounds of type XLII. The couplingreactions can be carried out by methods known to those skilled in theart. A typical set of reaction conditions includes reacting the indoleof structure AI1 with an acetylene compound AI2 in the presence of asource of palladium, a copper co-catalyst and an amine source andcarrying out the reaction at a temperature range of ambient to 150° C.

Compounds of the present invention, represented by structure XLIII andXLIV can be prepared as described in scheme AJ below.

Nitroanilines of structure AJ1 can be converted to indoles of structureXLIII by condensation and cyclization with nitriles of structure AJ2.The reaction can be carried out in a suitable organic solvent, e.g., DMFor dioxane. Treatment of compounds of structure XLIII with a basefollowed by reaction with a reactive functional group R₉ containing asuitable leaving group L can give the compounds of formula XLIV.

Compounds of formula I, represented by structure XLV-XLVIII can beprepared as shown in Scheme AK.

2-aminoindoles of structure XLV can be alkylated with a reactivefunctional group R₁₅ containing a suitable leaving group L in thepresence of a base, e.g., sodium hydride or potassium carbonate in asuitable organic solvent to give compounds of structure XLVI. A secondalkylation utilizing a reactive functional group R′₁₅ containing asuitable leaving group L similarly can give compounds of structureXLVII.

Acylation of compounds of structure XLV with acyl chlorides of structureAK1 can give compounds of structure XLVIII. The reaction is typicallycarried out in the presence of an organic base, e.g., a trialkylamine oran inorganic base, e.g., potassium carbonate in a suitable organicsolvent.

Compounds of the present invention, represented by structure XLIX can beprepared as described in scheme AL below.

Indole-3-carboxylic acids of structure AL1 can be activated to givecompounds of structure AL2. Compounds of structure AL2 can represent,for example, acyl halides or carboxylic acids activated with a reagentsuch as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Reactionof compounds of structure AL2 with hydroxyamidines of structure AL3 cangive O-acylhydroxyamidines AL4. Hydroxyamidines may be obtainedcommercially or by treatment of nitrile compounds with hydroxyamine.Heating compounds of structure AL4 in a non-reactive organic solvent,e.g., toluene, dichloroethane or dioxane in a temperature range of 30°C. to 150° C. can give compounds of structure XLIX.

Compounds of formula I, represented by structure XLX can be prepared asshown in Scheme AM.

Compounds of formula AM1 (in which R₁₇, defined above, is 1-3substituents placed on the indole) when treated with a base, copper (I)iodide and a substituted amine (Z-NH₂ where Z is defined above) toprovide compounds of structure AM2. Acylation with 2-chloroacetylchloride and a base such as triethylamine in solvents such as but notlimited to dichloromethane, tetrahydrofuran or toluene at temperaturesfrom ambient to reflux provides intermediate AM3 which is subsequentlycyclized to form compounds of structure AM4 employing palladium (II)acetate as catalyst, a phosphine ligand and a base such as triethylaminein solvents such as but not limited to tetrahydrofuran,dimethylformamide or toluene at temperatures from ambient to reflux.Reduction and elimination with a hydride source such as DIBAL-H insolvents such as but not limited to dichloromethane, tetrahydrofuran ortoluene at temperatures from 0° C. to reflux provides intermediate AM5.The subsequent steps leading to product XLX are described above.

Compounds of formula I, represented by structure XLXI can be prepared asshown in Scheme AN.

Compounds of formula AN1 can be treated with a triflate source, such astriflic anhydride, and a base, such as pyridine, in solvents such as butnot limited to tetrahydrofuran, dichloromethane or toluene attemperatures from ambient to reflux to provide intermediate AN2. AN2 caneither be directly reacted with palladium (0) and a R₁₂ substitutedtrialkyl tin compound in the presence of cesium fluoride and copper (I)iodide in solvents such as but not limited to tetrahydrofuran,dimethylformamide or toluene at temperatures from ambient to reflux toprovide product XLXI or reacted in a two step sequence of coupling witha pinacol borane source, such as bis-pinacol diborane, in the presenceof palladium (II) and a base, such as potassium acetate, in solventssuch as but not limited to tetrahydrofuran, dioxane or toluene attemperatures from ambient to reflux to provide AN3 and then a secondcoupling with palladium (0), cesium fluoride and an appropriate R₁₂Lcompound in solvents such as but not limited to tetrahydrofuran,dimethoxy ethane or toluene at temperatures from ambient to reflux wouldprovide XLXI.

C. METHODS OF THE INVENTION

Another aspect of the invention relates to a method for treatingHepatitis C viral (HCV) infection in a subject in need thereof,comprising administering to the subject an effective amount of one ormore compound(s) of formula I or one or more pharmaceutically acceptablesalt(s) thereof, or a pharmaceutical composition comprising an effectiveamount of one of more compound(s) of formula I or one or morepharmaceutically acceptable salt(s) thereof, as described above.

As used herein, the term “treating” refers to: (i) preventing a disease,disorder or condition from occurring in a subject that may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it; (ii) inhibiting a disease, disorder orcondition, i.e., arresting its development; and/or (iii) relieving adisease, disorder or condition, i.e., causing regression of the disease,disorder and/or condition.

As used herein, the term “subject” refers to an animal or any livingorganism having sensation and the power of voluntary movement, and whichrequires for its existence oxygen and organic food. Nonlimiting examplesinclude members of the human, equine, porcine, bovine, murine, canineand feline species. In some embodiments, the subject is a mammal or awarm-blooded vertebrate animal. In other embodiments, the subject is ahuman. As used herein, the term “patient” may be used interchangeablywith “human”.

Without being limited to any particular theory, it is believed that thecompounds of the present invention inhibit IRES-mediated initiation,elongation and termination, i.e., translation by interfering withfunction of the IRES directly and/or with the interaction of the IRESand a cellular and/or viral factor. Thus, another aspect of theinvention relates to a method for treating an infection by a wild typevirus or a virus that is resistant to a currently available antiviralagent, in a subject in need thereof, wherein the wild type or resistantvirus comprises an internal ribosome entry site (IRES), comprisingadministering to the subject an effective amount of one or morecompound(s) of the invention or one or more pharmaceutically acceptablesalt(s) thereof, or a pharmaceutical composition comprising an effectiveamount of one of more compound(s) of the invention or one or morepharmaceutically acceptable salt(s) thereof, as described above.Nonlimiting examples of such virus include viruses of the picornavirusgenus, such as poliovirus, hepatitis A virus, coxsackievirus andrhinovirus; viruses of the coronaviridae genus, such as SARS; viruses ofthe arbovirus genus; viruses of the flavivirus genus, such as yellowfever, dengue, and West Nile virus; herpesviruses, such as herpessimplex virus and Kaposi's sarcoma-associated herpesvirus, and otherviruses with a similar mode of replication; and HIV, human leukemiaviruses (HTLV) and other viruses with a similar mode of translation.

Yet another aspect of the invention relates to a method for inhibitingHCV IRES-mediated initiation, translation and/or replication in asubject in need thereof, comprising administering to the subject aneffective amount of one or more compound(s) of formula I or one or morepharmaceutically acceptable salt(s) thereof, or a pharmaceuticalcomposition comprising an effective amount of one of more compound(s) offormula I or one or more pharmaceutically acceptable salt(s) thereof, asdescribed above.

Some methods of the present invention comprise administering one or morecompound(s) of formula I, or a pharmaceutical composition comprising oneor more compound(s) of formula I wherein:

-   X is:-   a nitro group;-   a cyano group;-   a —COR_(a) group, where R_(a) is:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or a halogen, or

a dialkyl-amino;

-   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;-   a formyl group;-   a C₆ to C₈ aryl optionally substituted with an alkoxy; or-   a 5 or 6-membered heteroaryl optionally substituted with:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or one or morehalogen(s), or

a 5 to 6 membered heteroaryl;

-   Y is:-   a haloalkyl;-   a halogen;-   an amino optionally substituted with one or more C₁ to C₆ alkyl(s);-   a benzofuran;-   a benzothiophene;-   a dibenzofuran;-   a dibenzothiophene;-   a benzothiazole;-   a naphthalene;-   an indole, optionally substituted on the nitrogen with a C₁ to C₆    alkyl;    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined    above, or an —SO₂R_(x), where R_(x) is as defined above; or    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;-   a —NHCOR_(e) group, where R_(e) is:

a C₁ to C₆ alkyl;

a C₆ to C₈ aryl optionally substituted with:

-   -   a C₁ to C₆ alkyl,    -   an alkoxy,    -   a cyano group,    -   a nitro group, or    -   a halogen;

-   a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;

-   a —NR_(g)R_(h) group, where R₉ is a C₁ to C₆ alkyl or a hydrogen and    Rh is a C₆ to C₈ aryl optionally substituted with an alkoxy;

-   a C₁ to C₆ alkyl;

-   a 5 or 6 membered heteroaryl, optionally substituted with:

a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,

a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where R_(x) isas defined above, or

an amino group;

-   a 5 or 6 membered heterocycle optionally substituted with:

a —COOR_(x) group, where R_(x) is as defined above, or

a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a C₆ to C₈ aryl, optionally substituted with one or more of the    following:

an alkoxy, optionally substituted with:

an alkoxy,

-   -   a hydroxy,    -   one or more halogen(s),    -   a 5 or 6 membered heterocycle, optionally substituted with:        -   a C₁ to C₆ alkyl, or        -   a hydroxy,    -   an amino group optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and        R_(i) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —NR_(j)COR_(k) group, where R_(k) is:        -   a C₁ to C₆ alkyl,        -   a hydrogen, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),    -   and R_(j) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —N═N⁺═N⁻ group, or    -   a —COR₁, where R₁ is a 5 or 6 membered heterocycle optionally        substituted with a hydroxy,

an amino optionally substituted with one or more C₁ to C₆ alkyl(s),

a nitro group,

a C₁ to C₆ alkyl group, optionally substituted with:

-   -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or    -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,

a haloalkoxy,

a halogen,

a hydroxy,

a —COOR_(x) group, where R_(x) is as defined above,

a —COR_(m) group, where R_(m) is:

-   -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), where the one or more C₁ to C₆ alkyl(s) is/are        optionally substituted with:        -   a hydroxy        -   a 5 or 6 membered heterocycle,        -   an amino optionally substituted with one or more C₁ to C₆            alkyls,    -   and/or        -   an alkoxy,    -   a 3 to 7 membered heterocycle, optionally substituted with a C₁        to C₆ alkyl, optionally substituted with a dialkyl-amino,    -   a —NHR_(n) group, where R_(n) is:        -   a —CH₂CONH₂, or        -   a C₆ to C₈ aryl optionally substituted with:            -   an alkyl,            -   one or more halogen(s),            -   a nitro group, or            -   one or more alkoxy(s),

a —NR_(o)COR_(p) group, where R_(p) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   an alkoxy, or        -   a C₆ to C₈ aryl,    -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with a halogen,    -   a 5 or 6 membered heteroaryl optionally substituted with one or        more C₁ to C₆ alkyl(s),    -   a hydrogen,        and where R_(o) is:    -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a haloalkyl,    -   a haloalkoxy, or    -   a —COR_(x) group, where R_(x) is as defined above,

and where R_(r) is:

-   -   a C₆ to C₈ aryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a C₁ to C₆ alkyl optionally substituted with one or more of the        following:        -   a halogen,        -   an alkylene,        -   a C₆ to C₈ aryl, and/or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a —COOR_(x) group, where R_(x) is as defined above,

a —NR_(t)COOR_(u) group, where R_(u) is:

-   -   a C₁ to C₁₂ alkyl, optionally substituted with:        -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆ alkyl            or an alkoxy,        -   an alkylene,        -   an alkoxy,        -   an alkyne,        -   a halogen, or        -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with:        -   an alkoxy,        -   a halogen, or        -   a C₁ to C₆ alkyl, or    -   a 5 or 6 membered heterocycle,

and R_(t) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(v)SO₂R_(w) group, where R_(v) is:

-   -   a hydrogen,    -   a —COR_(x), where R_(x) is as defined above, or    -   a C₁ to C₆ alkyl, optionally substituted with:        -   a halogen,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a —OCOR_(x) group, where R_(x) is as defined above,        -   a hydroxy, or        -   an alkoxy,

and where R_(w) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   a haloalkyl,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle,    -   a C₂ to C₆ alkylene,    -   an alkyl- or dialkyl-amino optionally substituted with a        halogen,    -   a 5 or 6 membered heterocycle, or    -   a 5 or 6 membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a 5 or 6 membered heterocycle, or            optionally substituted with a C₁ to C₆ alkyl, where R_(y) is            a C₁ to C₆ alkyl or hydrogen,

where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally substituted witha C₆ to C₈ aryl,

a —SR_(x) group, where R_(x) is as defined above,

a —SO₂R_(aa) group, where R_(aa) is:

-   -   a C₁ to C₆ alkyl,    -   an amino group,    -   an alkyl- or dialkyl-amino group optionally substituted with a        hydroxy or a —COOR_(x) group, where R_(x) is as defined above,    -   a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, and/or

a —NHR_(bb) group, where R_(bb) is:

-   -   a —C(═S)NH₂ group, or    -   a —PO(OR_(x))₂ group, where R_(x) is as defined above;        group, where R_(cc) is:

a naphthalene,

a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing:

-   -   an alkoxy,    -   a hydroxy,    -   a halogen,    -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,    -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen or a        C₁ to C₆ alkyl, optionally substituted with a halogen, and        R_(ff) is:        -   a hydrogen,        -   a haloalkyl,        -   a haloalkoxy,        -   a C₁ to C₆ alkyl, or        -   a —COR_(x), where R_(x) is as defined above,    -   a —NR_(gg)COR_(hh) group, where R_(hh) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl optionally substituted with:            -   an alkoxy,            -   a halogen, or            -   an amino optionally substituted with one or more C₁ to                C₆ alkyl(s),        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s), where the alkyls are optionally substituted with a            halogen,        -   a 5 or 6 membered heterocycle,        -   a 5 or 6 membered heteroaryl,    -   and R_(gg) is:        -   a hydrogen,        -   a C₁ to C ₆ alkyl,        -   a haloalkyl,        -   a haloalkoxy, or        -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl,    -   5 or 6 membered heterocycle groups,    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), and/or    -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above, and        R_(ii) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a haloalkoxy,        -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:

-   a C₁ to C₆ alkyl optionally substituted with:

an alkoxy,

one or more halogen(s), or

a C₆ to C₈ aryl;

-   a C₂ to C₆ alkylene;-   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or more    C₁ to C₆ alkyl(s);-   a —COOR_(x) group, where R_(x) is as defined above; or-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:-   a hydrogen;-   a hydroxy;-   a halogen;-   a haloalkyl;-   a nitro group;-   a 5 or 6 membered heteroaryl;-   a 5 or 6 membered heterocycle;-   an alkoxy optionally substituted with:

one or more halogen(s),

a C₆ to C₈ aryl, or

a 5 or 6 membered heterocycle;

-   a C₆ to C₈ aryl optionally substituted with an alkoxy;-   a —COR_(x) group, where R_(x) is as defined above;-   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or a 5    or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:-   R₂ is:-   a nitro group;-   a hydrogen;-   a halogen;-   a hydroxy group;-   a C₁ to C₆ alkyl group, optionally substituted with one or more    halogen(s);-   an amino group;-   an alkoxy group optionally substituted with:

one or more halogen(s),

an —OCOR_(x) group, where R_(x) is as defined above,

a dialkyl-amino optionally substituted with an alkoxy,

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl,

a 5 or 6 membered heteroaryl group, or

a C₆ to C₈ aryl group;

-   a —COOR_(x) group, where R_(x) is as defined above;-   a haloalkyl;-   an amide group optionally substituted with:

a hydroxy group, or

a C₆ to C₈ aryl;

-   a 5 or 6 membered heteroaryl;-   a —OCOR_(x) group, where R_(x) is as defined above;-   a —NHCOR_(jj) group, where R_(jj) is:

an alkoxy, or

an amino optionally substituted with one or more C₁ to C₆ alkyl(s);

-   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;-   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:-   R₃ is:-   a hydrogen; or-   CH₂OCOR_(x), and R_(x) is as defined above.

As used herein, the term “effective amount” refers to the amountrequired to produce a desired effect. For example, the effective amountmay be the amount required to treat a Hepatitis C viral (HCV) infection,the amount required to treat an infection by a virus which comprises aninternal ribosome entry site (IRES), the amount required to inhibit HCVIRES-mediated initiation and/or translation, or the amount required toinhibit viral replication or infectivity, in a subject or, morespecifically, in a human. In some instances, the desired effect can bedetermined by analyzing (1) the presence of HCVRNA; (2) the presence ofanti-HCV antibodies; (3) the level of serum alanine amino transferase(ALT) and aspartate aminotransferase (AST) (ALT and AST are elevated inpatients chronically infected with HCV); (4) hepatocellular damageresulting from HCV infection, including steatosis, fibrosis andcirrhosis; (5) hepatocellular carcinoma as a result of chronic HCVinfection; and (5) extrahepatic sequelae (non-limiting examples includepruritis, encephalopathies, mental disorders such as anxiety ordepression) of infection with HCV or other viruses which contain an IRESelement. The effective amount for a subject will depend upon variousfactors, including the subject's body weight, size and health. Effectiveamounts for a given patient can be determined by routine experimentationthat is within the skill and judgment of the clinician.

For any compound, the effective amount can be estimated initially eitherin cell culture assays or in relevant animal models, such aschimpanzees, marmosets and tamarins. The animal model may also be usedto determine the appropriate concentration range and route ofadministration. Such information can then be used to determine usefuldoses and routes for administration in humans. Therapeutic efficacy andtoxicity may be determined by standard pharmaceutical procedures in cellcultures or experimental animals, e.g., ED₅₀ (the dose therapeuticallyeffective in 50% of the population) and LD₅₀ (the dose lethal to 50% ofthe population). The dose ratio between therapeutic and toxic effects isthe therapeutic index, and it can be expressed as the ratio, LD₅₀/ED₅₀.In some embodiments, the effective amount is such that a largetherapeutic index is achieved. In further embodiments, the dosage iswithin a range of circulating concentrations that include an ED₅₀ withlittle or no toxicity. The dosage may vary within this range dependingupon the dosage form employed, sensitivity of the patient, and the routeof administration.

More specifically, the concentration-biological effect relationshipsobserved with regard to the compound(s) of the present inventionindicate an initial target plasma concentration ranging fromapproximately 0.1 μg/mL to approximately 100 μg/mL, from approximately 1μg/mL to approximately 50 μg/mL, from approximately 5 μg/mL toapproximately 50 μg/mL, or from approximately 10 μg/mL to approximately25 μg/mL. To achieve such plasma concentrations, the compounds of theinvention may be administered at doses that vary from 0.1 μg to 100,000mg, depending upon the route of administration. Guidance as toparticular dosages and methods of delivery is provided in the literatureand is generally available to practitioners in the art. In general, thedose will be in the range of about 1 mg/day to about 10 g/day, or about0.1 g to about 3 g/day, or about 0.3 g to about 3 g/day, or about 0.5 gto about 2 g/day, in single, divided, or continuous doses for a patientweighing between about 40 to about 100 kg (which dose may be adjustedfor patients above or below this weight range, particularly childrenunder 40 kg).

The exact dosage will be determined by the practitioner, in light offactors related to the subject. Dosage and administration may beadjusted to provide sufficient levels of the active agent(s) or tomaintain the desired effect. Factors which may be taken into accountinclude the severity of the disease state, general health of thesubject, ethinicity, age, weight, and gender of the subject, diet, timeand frequency of administration, drug combination(s), reactionsensitivities, experience with other HCV therapies, andtolerance/response to therapy. Long-acting pharmaceutical compositionsmay be administered every 3 to 4 days, every week, or once every twoweeks depending on half-life and clearance rate of the particularformulation.

The compounds and compositions of the present invention may beadministered to the subject via any drug delivery route known in theart. Nonlimiting examples include oral, ocular, rectal, buccal, topical,nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus andinfusion), intracerebral, transdermal, and pulmonary routes ofadministration.

D. METABOLITES OF THE COMPOUNDS OF THE INVENTION

Also falling within the scope of the present invention are the in vivometabolic products of the compounds described herein. Such products mayresult, for example, from the oxidation, reduction, hydrolysis,amidation, esterification and the like of the administered compound,primarily due to enzymatic processes. Accordingly, the inventionincludes compounds produced by a process comprising contacting acompound of this invention with a mammalian tissue or a mammal for aperiod of time sufficient to yield a metabolic product thereof. Suchproducts typically are identified by preparing a radio-labeled (e.g. C¹⁴or H³) compound of the invention, administering it in a detectable dose(e.g., greater than about 0.5 mg/kg) to a mammal such as rat, mouse,guinea pig, monkey, or to man, allowing sufficient time for metabolismto occur (typically about 30 seconds to 30 hours), and isolating itsconversion products from urine, blood or other biological samples. Theseproducts are easily isolated since they are labeled (others are isolatedby the use of antibodies capable of binding epitopes surviving in themetabolite). The metabolite structures are determined in conventionalfashion, e.g., by MS or NMR analysis. In general, analysis ofmetabolites may be done in the same way as conventional drug metabolismstudies well-known to those skilled in the art. The conversion products,so long as they are not otherwise found in vivo, are useful indiagnostic assays for therapeutic dosing of the compounds of theinvention even if they possess no biological activity of their own.

E. PHARMACEUTICAL COMPOSITIONS OF THE INVENTION

Yet another aspect of the invention relates to a pharmaceuticalcomposition comprising: (i) an effective amount of one or morecompound(s) of formula I or one or more pharmaceutically acceptablesalt(s) thereof, as described above; and (ii) one or morepharmaceutically acceptable excipient(s).

In some embodiments, the pharmaceutical composition comprises one ormore compound(s) of formula I wherein:

-   X is:-   a nitro group;-   a cyano group;-   a —COR_(a) group, where R_(a) is:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or a halogen, or

a dialkyl-amino;

-   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;-   a formyl group;-   a C₆ to C₈ aryl optionally substituted with an alkoxy; or-   a 5 or 6-membered heteroaryl optionally substituted with:

a C₁ to C₆ alkyl,

a C₆ to C₈ aryl optionally substituted with an alkoxy or one or morehalogen(s), or

a 5 to 6 membered heteroaryl;

-   Y is:-   a haloalkyl;-   a halogen;-   an amino optionally substituted with one or more C₁ to C₆ alkyl(s);-   a benzofuran;-   a benzothiophene;-   a dibenzofuran;-   a dibenzothiophene;-   a benzothiazole;-   a naphthalene;-   an indole, optionally substituted on the nitrogen with a C₁ to C₆    alkyl;    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined    above, or an —SO₂R_(x), where R_(x) is as defined above; or    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;-   a —NHCOR_(e) group, where R_(e) is:

a C₁ to C₆ alkyl;

a C₆ to C₈ aryl optionally substituted with:

-   -   a C₁ to C₆ alkyl,    -   an alkoxy,    -   a cyano group,    -   a nitro group, or    -   a halogen;

-   a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;

-   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a hydrogen    and R_(h) is a C₆ to C₈ aryl optionally substituted with an alkoxy;

-   a C₁ to C₆ alkyl;

-   a 5 or 6 membered heteroaryl, optionally substituted with:

a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,

a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where R_(x) isas defined above, or

an amino group;

-   a 5 or 6 membered heterocycle optionally substituted with:

a —COOR_(x) group, where R_(x) is as defined above, or

a —NHCOOR_(x) group, where R_(x) is as defined above;

-   a C₆ to C₈ aryl, optionally substituted with one or more of the    following:

an alkoxy, optionally substituted with:

-   -   an alkoxy,    -   a hydroxy,    -   one or more halogen(s),    -   a 5 or 6 membered heterocycle, optionally substituted with:        -   a C₁ to C₆ alkyl, or        -   a hydroxy,    -   an amino group optionally substituted with one or more C₁ to C₆        alkyl(s),    -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and        R_(i) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —NR_(j)COR_(k) group, where R_(k) is:        -   a C₁ to C₆ alkyl,        -   a hydrogen, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),    -   and R_(j) is:        -   a hydrogen,        -   a C₁ to C₆ alkyl,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a haloalkyl, or        -   a haloalkoxy,    -   a —N═N⁺═N⁻ group, or    -   a —COR₁, where R₁ is a 5 or 6 membered heterocycle optionally        substituted with a hydroxy,

an amino optionally substituted with one or more C₁ to C₆ alkyl(s),

a nitro group,

a C₁ to C₆ alkyl group, optionally substituted with:

-   -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or    -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,

a haloalkoxy,

a halogen,

a hydroxy,

a —COOR_(x) group, where R_(x) is as defined above,

a —COR_(m) group, where R_(m) is:

-   -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), where the C₁ to C₆ alkyls are optionally substituted        with:        -   a hydroxy        -   a 5 or 6 membered heterocycle,        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),        -   an alkoxy,    -   a 3 to 7 membered heterocycle, optionally substituted with a C₁        to C₆ alkyl, optionally substituted with a dialkyl-amino,    -   a —NHR_(n) group, where R_(n) is:        -   a —CH₂CONH₂, or        -   a C₆ to C₈ aryl optionally substituted with:            -   an alkyl,            -   one or more halogen(s),            -   a nitro group, or            -   one or more alkoxy(s),

a —NR_(o)COR_(p) group, where R_(p) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   an alkoxy, or        -   a C₆ to C₈ aryl,    -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with a halogen,    -   a 5 or 6 membered heteroaryl optionally substituted with one or        more C₁ to C₆ alkyl(s),    -   a hydrogen,

and where R_(o) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a haloalkyl,    -   a haloalkoxy, or    -   a —COR_(x) group, where R_(x) is as defined above,

and where R_(r) is:

-   -   a C₆ to C₈ aryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a haloalkyl,        -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a C₁ to C₆ alkyl optionally substituted with one or more of the        following:        -   a halogen,        -   an alkylene,        -   a C₆ to C₈ aryl, and/or        -   a —COOR_(x) group, where R_(x) is as defined above,    -   a —COOR_(x) group, where R_(x) is as defined above,

a —NR_(t)COOR_(u) group, where R_(u) is:

-   -   a C₁ to C₁₂ alkyl, optionally substituted with:        -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆ alkyl            or an alkoxy,        -   an alkylene,        -   an alkoxy,        -   an alkyne,        -   a halogen, or        -   a 5 or 6 membered heterocycle,    -   a C₆ to C₈ aryl, optionally substituted with:        -   an alkoxy,        -   a halogen, or        -   a C₁ to C₆ alkyl, or    -   a 5 or 6 membered heterocycle,

and R_(t) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a —COR_(x) group, where R_(x) is as defined above,    -   a haloalkyl, or    -   a haloalkoxy,

a —NR_(v)SO₂R_(w) group, where R_(v) is:

-   -   a hydrogen,    -   a —COR_(x), where R_(x) is as defined above, or    -   a C₁ to C₆ alkyl, optionally substituted with:        -   a halogen,        -   a —COR_(x) group, where R_(x) is as defined above,        -   a —OCOR_(x) group, where R_(x) is as defined above,        -   a hydroxy, or        -   an alkoxy,

and where R_(w) is:

-   -   a C₁ to C₆ alkyl optionally substituted with:        -   a halogen,        -   a haloalkyl,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle,    -   a C₂ to C₆ alkylene,    -   an alkyl- or dialkyl-amino optionally substituted with a        halogen,    -   a 5 or 6 membered heterocycle, or    -   a 5 or 6 membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a 5 or 6 membered heterocycle, or            optionally substituted with a C₁ to C6 alkyl where R_(y) is            a C₁ to C₆ alkyl or hydrogen,            where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally            substituted with a C₆ to C₈ aryl.

-   a —SR_(x) group, where R_(x) is as defined above,

-   a —SO₂R_(aa) group, where R_(aa) is:

a C₁ to C₆ alkyl,

an amino group,

an alkyl- or dialkyl-amino group optionally substituted with a hydroxyor a —COOR_(x) group, where R_(x) is as defined above,

a 5 or 6 membered heteroaryl,

-   a C₆ to C₈ aryl, and/or-   a —NHR_(bb) group, where R_(bb) is:

a —C(═S)NH₂ group, or

a —PO(OR_(x))₂ group, where R_(x) is as defined above;

group, where R_(cc) is:

-   a naphthalene,-   a 5 or 6 membered heteroaryl,-   a C₆ to C₈ aryl, optionally substituted with one or more of the    following:

an alkoxy,

a hydroxy,

a halogen,

a C₁ to C₆ alkyl, optionally substituted with a cyano group,

an amino optionally substituted with one or more C₁ to C₆ alkyl(s),

a —NHPOR_(x)R_(x), where R_(x) is as defined above,

a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen or a C₁ toC₆ alkyl, optionally substituted with a halogen, and R_(ff) is:

-   -   a hydrogen,    -   a haloalkyl,    -   a haloalkoxy,    -   a C₁ to C₆ alkyl, or    -   a —COR_(x), where R_(x) is as defined above,

a —NR_(gg)COR_(hh) group, where R_(hh) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl optionally substituted with:        -   an alkoxy,        -   a halogen, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyl(s),    -   an amino optionally substituted with one or more C₁ to C₆        alkyl(s), where the alkyls are optionally substituted with a        halogen,    -   a 5 or 6 membered heterocycle,    -   a 5 or 6 membered heteroaryl,

and R_(gg) is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a haloalkyl,    -   a haloalkoxy, or    -   a —COR_(x) group, where R_(x) is as defined above,

a haloalkyl,

5 or 6 membered heterocycle groups,

an amino optionally substituted with one or more C₁ to C₆ alkyl(s),and/or

a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above, and R_(ii)is:

-   -   a hydrogen,    -   a C₁ to C₆ alkyl,    -   a haloalkyl,    -   a haloalkoxy,    -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:

-   a C₁ to C₆ alkyl optionally substituted with:

an alkoxy,

one or more halogen(s), or

a C₆ to C₈ aryl;

-   a C₂ to C₆ alkylene;-   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or more    C₁ to C₆ alkyl(s);-   a —COOR_(x) group, where R_(x) is as defined above; or-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:-   a hydrogen;-   a hydroxy;-   a halogen;-   a haloalkyl;-   a nitro group;-   a 5 or 6 membered heteroaryl;-   a 5 or 6 membered heterocycle;-   an alkoxy optionally substituted with:

one or more halogen(s),

a C₆ to C₈ aryl, or

a 5 or 6 membered heterocycle;

-   a C₆ to C₈ aryl optionally substituted with an alkoxy;-   a —COR_(x) group, where R_(x) is as defined above;-   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or a 5    or 6 membered heterocycle;-   or-   R₁ joins together with R₂ to form:-   R₂ is:-   a nitro group;-   a hydrogen;-   a halogen;-   a hydroxy group;-   a C₁ to C₆ alkyl group, optionally substituted with one or more    halogen(s);-   an amino group;-   an alkoxy group optionally substituted with:

one or more halogen(s),

an —OCOR_(x) group, where R_(x) is as defined above,

a dialkyl-amino optionally substituted with an alkoxy,

a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl,

a 5 or 6 membered heteroaryl group, or

a C₆ to C₈ aryl group;

-   a —COOR_(x) group, where R_(x) is as defined above;-   a haloalkyl;-   an amide group optionally substituted with:

a hydroxy group, or

a C₆ to C₈ aryl;

-   a 5 or 6 membered heteroaryl;-   a —OCOR_(x) group, where R_(x) is as defined above;-   a —NHCOR_(jj) group, where R_(jj) is:

an alkoxy, or

an amino optionally substituted with one or more C₁ to C₆ alkyl(s);

-   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;-   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:-   R₃ is:-   a hydrogen; or-   —CH₂OCOR_(x), and R_(x) is as defined above;-   provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is    alkyl, R is hydrogen, R₁ is hydrogen or hydroxy, R₂ is hydrogen or    hydroxy, and R₃ is hydrogen, then Z is:-   a C₁ to C₆ alkyl substituted with:

an alkoxy,

one or more halogen(s), or

a C₆ to C₈ aryl;

-   a C₂ to C₆ alkylene;-   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or more    C₁ to C₆ alkyl(s);-   a —COOR_(x) group, where R_(x) is as defined above; or

or one or more pharmaceutically acceptable salt(s) thereof.

The pharmaceutical composition may be formulated to achieve aphysiologically compatible pH, ranging from a pH of about 3 to a pH ofabout 11. In some embodiments, the pharmaceutical composition isformulated to achieve a pH of about 3 to a pH of about 7. In otherembodiments, the pharmaceutical composition is formulated to achieve apH of about 5 to a pH of about 8.

The pharmaceutical composition may comprise a combination of compoundsof the present invention, or may include a second active ingredientuseful in the treatment of viral infections, such as anti-viral agentsthat include, but are not limited to: pegylated interferon, including byway of non-limiting example pegylated α-interferon; un-pegylatedinterferon, including by way of non-limiting example, un-pegylatedα-interferon; ribavirin or prodrugs or derivatives thereof; proteaseinhibitors; polyermase inhibitors; p7 inhibitors; entry inhibitors,including fusion inhibitors such as Fuzeon™ (Trimeris); helicaseinhibitors; a Toll-like receptor agonist, a caspase inhibitor,anti-fibrotics; drugs that target IMPDH (inosine monophosphatedehydrogenase inhibitors), such as Merimepadib™ (Vertex PharmaceuticalsInc.); synthetic thymosin alpha 1 (ZADAXIN™, SciClone PharmaceuticalsInc.); a glycosidase inhibitor; a glucosidase inhibitor; therapeuticviral vaccines, such as those produced by Chiron and Immunogenics; andimmunomodulators, such as histamine, antibodies against HCV, such asXTL-6865 and XTL-002 (XTL Biopharmaceuticals), antisense RNA, ribozymes,RNAi, and anti-HCV agents with unknown mechanism of action.

The term “pharmaceutically acceptable excipient” refers to an excipientfor administration of a pharmaceutical agent, such as the compounds ofthe present invention. The term refers to any pharmaceutical excipientthat may be administered without undue toxicity. Pharmaceuticallyacceptable excipients may be determined in part by the particularcomposition being administered, as well as by the particular mode ofadministration and/or dosage form. Nonlimiting examples ofpharmaceutically acceptable excipients include carriers, solvents,stabilizers, adjuvants, diluents, etc. Accordingly, there exists a widevariety of suitable formulations of pharmaceutical compositions of thepresent invention (see, e.g., Remington's Pharmaceutical Sciences).

Suitable excipients may be carrier molecules that include large, slowlymetabolized macromolecules such as proteins, polysaccharides, polylacticacids, polyglycolic acids, polymeric amino acids, amino acid copolymers,and inactive virus particles. Other exemplary excipients includeantioxidants such as ascorbic acid; chelating agents such as EDTA;carbohydrates such as dextrin, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water,saline, glycerol and ethanol; wetting or emulsifying agents; pHbuffering substances; and the like. Liposomes are also included withinthe definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions of the invention may be formulated inany form suitable for the intended method of administration. Suitableformulations for oral administration include solids, liquid solutions,emulsions and suspensions, while suitable inhaleable formulations forpulmonary administration include liquids and powders. Alternativeformulations include syrups, creams, ointments, tablets, and lyophilizedsolids which can be reconstituted with a physiologically compatiblesolvent prior to administration.

When intended for oral use for example, tablets, troches, lozenges,aqueous or oil suspensions, non-aqueous solutions, dispersible powdersor granules (including micronized particles or nanoparticles),emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions, and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation.

Pharmaceutically acceptable excipients suitable for use in conjunctionwith tablets include, for example, inert diluents, such as celluloses,calcium or sodium carbonate, lactose, calcium or sodium phosphate;disintegrating agents, such as croscarmellose sodium, cross-linkedpovidone, maize starch, or alginic acid; binding agents, such aspovidone, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample celluloses, lactose, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with non-aqueousor oil medium, such as glycerin, propylene glycol, polyethylene glycol,peanut oil, liquid paraffin or olive oil.

In other embodiments, pharmaceutical compositions of the invention maybe formulated as suspensions comprising one or more compound(s) of thepresent invention in admixture with at least one pharmaceuticallyacceptable excipient suitable for the manufacture of a suspension. Inyet other embodiments, pharmaceutical compositions of the invention maybe formulated as dispersible powders and granules suitable forpreparation of a suspension by the addition of one or more excipient(s).

Excipients suitable for use in connection with suspensions includesuspending agents, such as sodium carboxymethylcellulose,methylcellulose, hydroxypropyl methylcelluose, sodium alginate,polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wettingagents such as a naturally occurring phosphatide (e.g., lecithin), acondensation product of an alkylene oxide with a fatty acid (e.g.,polyoxyethylene stearate), a condensation product of ethylene oxide witha long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), acondensation product of ethylene oxide with a partial ester derived froma fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitanmonooleate); and thickening agents, such as carbomer, beeswax, hardparaffin or cetyl alcohol. The suspensions may also contain one or morepreservatives such as acetic acid, methyl and/or n-propylp-hydroxy-benzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth;naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids; hexitol anhydrides, such assorbitan monooleate; and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

Additionally, the pharmaceutical compositions of the invention may be inthe form of a sterile injectable preparation, such as a sterileinjectable aqueous emulsion or oleaginous suspension. Such emulsion orsuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, such as a solution in 1,2-propane-diol.The sterile injectable preparation may also be prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution, and isotonic sodium chloride solution. Inaddition, sterile fixed oils may be employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. In addition, fatty acids such as oleicacid may likewise be used in the preparation of injectables.

The compounds of the invention may be substantially insoluble in waterand sparingly soluble in most pharmaceutically acceptable proticsolvents and vegetable oils, but generally soluble in medium-chain fattyacids (e.g., caprylic and capric acids) or triglycerides and inpropylene glycol esters of medium-chain fatty acids. Thus, contemplatedin the invention are compounds which have been modified by substitutionsor additions of chemical or biochemical moieties which make them moresuitable for delivery (e.g., increase solubility, bioactivity,palatability, decrease adverse reactions, etc.), for example byesterification, glycosylation, PEGylation, etc.

In some embodiments, the compound of the invention is formulated fororal administration in a lipid-based composition suitable for lowsolubility compounds. Lipid-based formulations can generally enhance theoral bioavailability of such compounds. As such, pharmaceuticalcompositions of the invention may comprise a effective amount of one ormore compounds) of the invention, together with at least onepharmaceutically acceptable excipient selected from medium chain fattyacids or propylene glycol esters thereof (e.g., propylene glycol estersof edible fatty acids such as caprylic and capric fatty acids) andpharmaceutically acceptable surfactants, such as polyoxyl 40hydrogenated castor oil.

In alternative embodiments, the pharmaceutical composition may furthercomprise one or more aqueous solubility enhancer(s), such as acyclodextrin. Nonlimiting examples of cyclodextrin includehydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosylderivatives of α-, β-, and γ-cyclodextrin, andhydroxypropyl-β-cyclodextrin (HPBC). In some embodiments, thepharmaceutical composition further comprises about 0.1% to about 20%hydroxypropyl-β-cyclodextrin, about 1% to about 15%hydroxypropyl-β-cyclodextrin, or about 2.5% to about 10%hydroxypropyl-β-cyclodextrin. The amount of solubility enhancer employedmay depend on the amount of the compound of the present invention in thecomposition.

F. COMBINATION THERAPY

It is also possible to combine any compound of the present inventionwith one or more other active ingredients useful in the treatment of HCVinfection, including compounds, in a unitary dosage form, or in separatedosage forms intended for simultaneous or sequential administration to apatient in need of treatment. When administered sequentially, thecombination may be administered in two or more administrations. In analternative embodiment, it is possible to administer one or morecompounds of the present invention and one or more additional activeingredients by different routes.

The skilled artisan will recognize that a variety of active ingredientsmay be administered in combination with the compounds of the presentinvention that may act to augment or synergistically enhance the viralinhibiting activity of the compounds of the invention. Such activeingredients include anti-HCV agents. Anti-HCV agents include agents thattarget the virus as well as agents that have an immunomodulatory effect.For example, anti-HCV agents include, but are not limited to,interferon, including, for example without limitation, IFN-α, ribavirinor prodrugs or derivatives thereof; protease inhibitors, polymeraseinhibitors, helicase inhibitors, a Toll-like receptor agonist, a caspaseinhibitor and a glycosidase inhibitor, antibodies against HCV, such asXTL-6865 and XTL-002 (XTL Biophatrmaceuticals), antisense RNA,ribozymes, RNAi, and anti-HCV agents with unknown mechanism of action.Furthermore, the compounds of the invention may also be administered incombination with other compounds that affect IRES activity.

According to the methods of the invention, the combination of activeingredients may be: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by any other combinationtherapy regimen known in the art. When delivered in alternation therapy,the methods of the invention may comprise administering or deliveringthe active ingredients sequentially, e.g., in separate solution,emulsion, suspension, tablets, pills or capsules, or by differentinjections in separate syringes. In general, during alternation therapy,an effective dosage of each active ingredient is administeredsequentially, i.e., serially, whereas in simultaneous therapy, effectivedosages of two or more active ingredients are administered together.Various sequences of intermittent combination therapy may also be used.

To assist in understanding the present invention, the following Examplesare included. The experiments relating to this invention should not, ofcourse, be construed as specifically limiting the invention and suchvariations of the invention, now known or later developed, which wouldbe within the purview of one skilled in the art are considered to fallwithin the scope of the invention as described herein and hereinafterclaimed.

It will be apparent to those skilled in the art that specificembodiments of the present invention may be directed to one, some or allof the above-indicated aspects as well as other aspects, and mayencompass one, some or all of the above- and below- indicatedembodiments, as well as other embodiments.

Other than in the working examples, or where otherwise indicated, allnumbers expressing quantities of ingredients, reaction conditions, andso forth used in the specification and claims are to be understood asbeing modified by the term “about”. Accordingly, unless indicated to thecontrary, such numbers are approximations that may vary depending uponthe-desired properties sought to be obtained by the present invention.At the very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalparameter should be construed in light of the number of significantdigits and ordinary rounding techniques.

While the numerical ranges and parameters setting forth the broad scopeof the invention are approximations, the numerical values set forth inthe working examples are reported as precisely as possible. Anynumerical value, however, inherently contains certain errors necessarilyresulting from the standard deviation found in their respective testingmeasurements.

EXAMPLES

The present invention is described in more detail with reference to thefollowing non-limiting examples, which are offered to more fullyillustrate the invention, but are not to be construed as limiting thescope thereof. The examples illustrate the preparation of certaincompounds of the invention, and the testing of these compounds in vitroand/or in vivo. Those of skill in the art will understand that thetechniques described in these examples represent techniques described bythe inventors to function well in the practice of the invention, and assuch constitute preferred modes for the practice thereof. However, itshould be appreciated that those of skill in the art should in light ofthe present disclosure, appreciate that many changes can be made in thespecific methods that are disclosed and still obtain a like or similarresult without departing from the spirit and scope of the invention.

Example 1 Preparation of Compounds of the Invention Example 1A:Preparation of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (compound 5)

Step A: A solution of 6-methoxyindole (10.0 g, 68.0 mmol) in DMF (120mL) is cooled to 0° C. and treated with chlorosulfonyl isocyanate (7.72mL, 88.4 mmol). After the addition, the reaction mixture is stirred atthis temperature for 1 h. The dark solution is poured into ice water(600 mL) and the light brown solid is collected by filtration, washedwith additional H₂O and dried to afford 9.9 g (85%) of6-methoxy-1H-indole-3-carbonitrile as a light brown solid. Step B: To asolution of 6-methoxy-1H-indole-3-carbonitrile (9.9 g, 57.6 mmol) in DMF(150 mL) is added NaH (60% dispersion in mineral oil, 3.45 g, 86.3mmol). The reaction mixture is stirred for 15 min and then ethyl iodide(5.53 mL, 69.1 mmol) is added and the mixture is stirred at roomtemperature overnight. The reaction mixture is then diluted with H₂O andextracted with EtOAc (2×). The organic phases are washed with H₂O (3×)and saturated NaCl and then dried and concentrated to a semi-solid. Thecrude product is purified via column chromatography on silica gel (200g) using CH₂Cl₂/hexanes (50-100%) as eluent to yield6-methoxy-1-ethyl-1H-indole-3-carbonitrile as a tan solid.

Utilizing steps A and B above and substituting different indoles andalkyl halides gives the following compounds: Compounds 43, 45, 51, 52,108, 109, 115, 118, 120, 123, 126, 179 and 714.

Example 1B: Preparation of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile(compound 9)

Step A: To a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile(2.85 g, 14.2 mmol), prepared by example 1A, step B, in CH₂Cl₂ (40 mL)is added a 1M solution of BBr₃ in CH₂Cl₂ (28.5 mL, 28.5 mmol) at 0° C.The mixture is allowed to warm to room temperature and kept for 2.5 h.The dark reaction mixture is then poured onto ice and sufficient 1M NaOHis added until the pH is 8-9. The product is extracted with CH₂Cl₂ (3×)and the combined organic phases are washed with saturated NaHCO₃, H₂Oand saturated NaCl. After drying over MgSO₄, the solution isconcentrated and the product is purified by chromatography(EtOAc/CH₂Cl₂, 0-10%) to afford 2.15 g (82%) of6-hydoxy-1-ethyl-1H-indole-3-carbonitrile as a yellow solid.

Step B: To a solution 6-hydoxy-1-ethyl-1H-indole-3-carbonitrile (80 mg,0.43 mmol) in 5 mL of methyl ethyl ketone is added anhydrous K₂CO₃ (71mg, 0.52 mmol) and iodoethane (0.05 mL, 0.60 mmol). After stirringovernight at reflux, the reaction mixture is cooled, diluted with H₂Oand extracted with EtOAc (3×). The combined organic phases are dried andconcentrated. Flash chromatography (CH₂Cl₂) gives 94 mg (100%) of6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.

In similar fashion, following steps A and B, above, the followingcompounds are also prepared: Compounds 6, 10, 11, 12 and 24.

Example 1C: Preparation of5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile(compound 44)

A mixture of p-iodoanisole (85 mg, 0.36 mmol), anhydrous K₃PO₄ (102 mg,0.48 mmol), CuI (4.6 mg, 0.024 mmol) and N,N′-Dimethylcyclohexane-1,2-diamine (14 mg, 0.096 mmol) is added to5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile (45 mg, 0.24 mmol), preparedas described by the method of example 1A, step A, in anhydrous toluene(0.4 mL). After heating at reflux for 24 h, the solvent is evaporatedunder vacuum. The residue is dissolved with CH₂Cl₂ (5 mL) and themixture is filtered. The filtrate is concentrated to afford crudeproduct, which is purified by silica gel chromatography usingEtOAc/petroleum ether (1:4) as eluent to yield5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile.

Utilizing the procedure above and substituting different aryl iodidesgives the following compounds: Compounds 4, 8, 102, 103, 111, 112, 117,119, 124, 125, 127, 154.

Example 1D: Preparation of1-ethyl-6-(pyrazin-2-yloxy)-1H-indole-3-carbonitrile (compound 13)

To a solution of 1-ethyl-6-hydroxy-1H-indole-3-carbonitrile (60 mg, 0.32mmol) prepared as described in example 1A, step A, in DMF (5 mL) isadded K₂CO₃ (55 mg, 0.40 mmol) and 2-chloropyridazine (45 mg, 0.40mmol). The mixture is heated at 110° C. for 18 h. After cooling to roomtemperature, the reaction mixture is diluted with H₂O and extracted withEtOAc (3×). The combined organic phases are washed with H₂O andsaturated NaCl, dried and concentrated. The product is isolated bychromatography (EtOAc/CH₂Cl₂, 1-3%) over silica gel to afford 76 mg(96%) of the title compound,1-ethyl-6-(pyrazin-2-yloxy)-1H-indole-3-carbonitrile, as an off-whitesolid.

Example 1E: Preparation of 3-cyano-1-ethyl-1H-indole-6-carboxylic acidphenylamide (compound 15)

Step A: A solution of methyl 3-cyano-1-ethyl-1H-indole-6-carboxylate(1.60 g, 7.02 mmol), prepared by the method described in example 1A frommethyl 1H-indole-6-carboxylate, in THF (35 mL) is treated with 1N NaOH(7.7 mL, 7.7 mmol) and heated at reflux for 2.5 h. After cooling to roomtemperature, most of the THF is removed and the solution is diluted withH₂O and extracted with ether (2×). The ether extracts are discarded. Theaqueous phase is then acidified with 6N HCl to pH 2 and then extractedwith EtOAc (3×). The EtOAc layers are combined, washed with saturatedNaCl and then dried and concentrated to afford 1.43 g (95%) of3-cyano-1-ethyl-1H-indole-6-carboxylic acid as a white solid.

Step B: A suspension of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid(0.42 g, 1.96 mmol) in CH₂Cl₂ (15 mL) is cooled to 0° C. The suspensionis treated with DMF (2 drops) and then oxalyl chloride (0.34 mL, 3.92mmol) is added via syringe during 2 minutes after which the ice bath isremoved and the reaction mixture is allowed to warm to ambienttemperature during 1.5 h during which time the reaction becomes a yellowsolution. The solution is then concentrated in vacuo to afford 0.46 g(quantitative yield) of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride asa yellow solid.

Step C: A suspension of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride(70 mg, 0.30 mmol) in THF (5 mL) is cooled to 0° C. and treated withaniline (0.08 mL, 0.90 mmol). After the addition, the reaction is warmedto ambient temperature and after stirring for an additional 16 hours,the reaction mixture is diluted with H₂O and extracted with EtOAc (2×).The combined organic phases are washed with saturated NaCl and thendried and concentrated to afford the product. Chromatography(EtOAc/CH₂Cl₂, 2/98) over silica gel gives 44 mg (51%) of3-cyano-1-ethyl-1H-indole-6-carboxylic acid phenylamide.

Utilizing essentially the procedure above gives the following compound:Compound 89.

Example 1F: Preparation of t-butyl(3-cyano-1-ethyl-1H-indol-6-yl)-carbamate (compound 16)

A solution of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid (0.60 g, 2.80mmol) from Example 1E, step A, in t-butanol (20 mL) is treated with Et₃N(0.46 mL, 3.36 mmol) and diphenylphosphoryl azide (0.73 mL, 3.36mmol)and then heated at reflux for 4 h. After cooling to room temperature,most of the t-butanol is removed in vacuo to give an oil, which is thendissolved in EtOAc. After washing with H₂O, the organic phase isback-extracted with EtOAc and the organic layers are combined and washedsequentially with additional H₂O, saturated NaHCO₃ and saturated NaCl.The organic phase is dried, concentrated and the resulting crude productis purified by chromatography over silica gel using EtOAc/CH₂Cl₂ (0-1%)to afford 0.52 g (65%) of t-butyl(3-cyano-1-ethyl-1H-indol-6-yl)-carbamate as a white solid.

The following compound is made in similar fashion: Compound 90.

Example 1Ga: Preparation of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile via Suzukiroute (compound 55)

Step A: A 2M solution of lithium diisopropyl amide in THF/hexanes(Acros) (3.9 mL, 7.8 mmol) is diluted with THF (5 mL) in a flame-driedflask. After cooling the reaction to −30° C., a solution of1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.30 g, 6.5 mmol) in THF (10mL) is added dropwise during 10 min, maintaining the temperature at −30°C. After stirring for an additional 30 min at this temperature, asolution of iodine (2.31 g, 9.1 mmol) in THF (5 mL) is added during 10min. After the addition, the reaction is warmed to ambient temperatureduring 1 h. The reaction is then diluted with ice-H₂O and extracted withEtOAc (2×). The combined organic phases are washed with 1M sodiumthiosulfate and saturated NaCl and then concentrated to a brown solid.Chromatography (CH₂Cl₂/hexanes, 1/1) over silica gel gives 1.31 g (62%)of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile as an off-whitesolid.

Step B: A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile(1.25 g, 3.83 mmol),4-(4,4,5,5-tetramethyl)-1,3-2-dioxaboralanyl-2-yl-aniline (0.96 g, 4.90mmol), CsF (1.46 g, 9.58 mmol) and Pd(PPh₃)₂Cl₂ (110 mg, 0.15 mmol) inDME (20 mL) is added to a flask and alternatively evacuated and flushedwith N₂. The reaction is then heated at reflux for 24 h and then cooledto room temperature. The reaction mixture is diluted with H₂O andextracted with EtOAc (2×). The combined organic phases are washed withH₂O and saturated NaCl and then dried over MgSO₄ and concentrated. Thecrude reaction mix is purified by flash chromatography on silica gelusing EtOAc/CH₂Cl₂ (5/95) as eluent to afford 765 mg (69%) of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile as a yellowsolid.

Utilizing essentially the same procedure described above andsubstituting different boronic acids gives the following compounds:Compounds 19, 20, 21, 22, 53, 63, 70, 71, 74, 76, 77, 79, 80, 100, 110,229, 239, 240, 247, 250, 254, 255, 256, 257, 258, 259, 260, 281, 282,283, 284, 286, 335, 336, 337, 338, 339, 347, 348, 426, 427, 428, 429,476, 543, 578, 758.

Example 1Gb: Preparation of2-(4-aminophenyl)-1-butyl-6-methoxy-1H-indole-3-carbonitrile viaalternative Suzuki route

To a solution of (i-Pr)₂NH (1.35 mL, 9.65 mmol) in THF (30 mL) cooled to−78° C. is added n-BuLi (3.7 mL, 2.5M in hexanes, 9.21 mmol) in oneportion. The acetone/dry ice bath is exchanged for ice/water bath andthe solution is stirred further for 40 min. The solution is cooled to−78° C. and solution of 1-butyl-6-methoxy-1H-indole-3-carbonitrile,prepared as in example 1A (2.0 g, 8.77 mmol) in THF (10 mL) is addeddropwise. This solution is stirred for 15 min at −78° C., following by20 min at −20° C. Trimethyl borate (1.0 mL, 8.77 mmol) is added, thereaction mixture is stirred for 15 min at −20° C. after which thecooling bath is removed and this solution is stirred further at roomtemperature for 1 h. A solution of K₃PO₄ is added (11.7 mL, 3M aqueoussolution, 35.1 mmol) followed by a solution of 4-iodoaniline (2.5 g,11.40 mmol) and PdCl₂dppf catalyst (640 mg, 0.88 mmol) in DMF (40 mL,plus a 5 mL rinse). The reaction mixture is stirred overnight (ca. 18 h)and then water (80 mL) is added and the product is extracted with EtOAc(3×50 mL). The combined organic fractions are dried over MgSO₄, filteredand concentrated under reduced pressure. The crude product is purifiedvia flush chromatography on silica gel (5→60% EtOAc/Hexanes as eluant)to afford the desired2-(4-aminophenyl)-1-butyl-6-methoxy-1H-indole-3-carbonitrile as a tansolid (2.4 g, 86% yield).

The following compounds are prepared in similar fashion utilizing otherindole and aryl and hereroaryl bromides and iodides: Compounds 656, 659,660, 661, 682, 683, 712, 731, 732, 733, 806, 807, 808, 809, 810, 811,812, 813, 814, 827.

Example 1Gc: Preparation of2-(4-aminophenyl)-6-methoxy-1-propyl-1H-indole-3-carbonitrile viaNegishi route

A nitrogen-purged flask fitted with a septum and a nitrogen needle ischarged with dry THF (all additions performed by syringe) (20 mL).Diisopropylamine (Aldrich Sure-Seal, 2.00 mL, 14.3 mmol) is added, andthe solution is cooled to 0° C. n-Butyllithium (8.50 mL of 1.6 Msolution in hexane, 13.6 mmol) is added slowly. The flask is allowed towarm to room temperature briefly, and then is cooled to −78° C. Aconcentrated THF solution of 6-methoxy-1-propyl-1H-indole-3-carbonitrile(2.77 g, 12.9 mmol; prepared analogously to compound 5 of Example 1A) isadded slowly, and the resulting solution is maintained at −78° C. for 30min. The flask is then transferred to a water-ice bath and allowed tocome to 0° C. for about 15 minutes. The solution is once again cooled to−78° C., and ZnCl₂ (0.5 M solution in THF, 27.0 mL, 13.5 mmol) is slowlyadded. A precipitate is observed at this point, which may be thebis(indole)zinc compound, but the solution becomes homogeneous when theentire volume of zinc chloride solution is added. After about 10minutes, the solution is allowed to come to room temperature, and a THFsolution (5 mL) of 4-iodoaniline (3.47 g, 15.8 mmol) andtriphenylphosphine (338 mg, 1.29 mmol) is added. The septum is removed,and solid Pd₂(dba)₃ (295 mg, 0.322 mmol) is added. A reflux condenser isfitted to the flask, and the solution is degassed by three successivecycles of vacuum pumping/N₂ purging. The solution is then heated toreflux overnight. After cooling to room temperature, the solution ispoured into 4 volumes of water, and 4 volumes of ethyl acetate areadded. The resulting mixture is vigorously stirred for 30 minutes, thenfiltered through celite (with ethyl acetate washing) to remove solid Zn-and Pd-containing material. The phases are separated, and the aqueousphase is extracted with more ethyl acetate. The organic phases arewashed in sequence with saturated brine, combined, dried over anhydroussodium sulfate, filtered and evaporated. A solid precipitate forms atthis point, which is sufficiently pure product and is collected bytrituration with ether and filtration. The remaining material ispurified by column chromatography (eluting 1:2 ethyl acetate-hexane onsilica gel 60). Total yield of the product,2-(4-amino-phenyl)-6-methoxy-1-propyl-1H-indole-3-carbonitrile, is 2.75g (8.99 mmol, 70%).

The following compounds are made using essentially the same procedureand substituting other aryl or heteroaryl iodides or bromides: Compounds393, 408, 430, 431, 436, 437, 438, 459, 460, 461, 462, 483, 484, 632,633, 634, 635, 636, 650, 651.

Example 1Gd: Preparation of1-ethyl-2-(3-hydroxyphenyl)-6-methoxy-1H-indole-3-carbonitrile (Compound288)

Step A: A solution of THF (60 mL) and diisopropylamine (5.5 mL, 39 mmol)is cooled to −78° C. n-Butyllithium (14.5 mL, 2.5M in hexanes, 36.2mmol) is added dropwise over 5 minutes. The LDA mixture is stirred at−78° C. for 10 minutes, and then at 0° C. for 20 minutes. The solutionis re-cooled to −78° C. 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (5.0g, 25 mmol), prepared as in example 1A, is taken up in THF (30 mL) andadded dropwise to the LDA mixture over 15 minutes. The reaction isstirred at −78° C. for 10 minutes, and at 0° C. for 30 minutes. Onceagain, the reaction mixture is cooled to −78° C. Tributyltin iodide (10mL, 35 mmol) is added dropwise. This is stirred at −78° C. for 15minutes, and then at 0° C. for 30 minutes. The reaction mixture isabsorbed onto silica gel and concentrated. Purification bychromatography (CH₂Cl₂) yields1-ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile (12.05 g,98%).

Step B: 1-Ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile(1.0 g, 2.05 mmol), prepared in step A, is combined with 3-iodophenol(474 mg, 2.15 mmol), Pd(PPh₃)₂Cl₂ (67 mg, 0.102 mmol), CuI (75 mg, 0.39mmol) and THF (4.0 mL). This mixture is heated at 65° C. overnight. Thereaction mixture is diluted in EtOAc, and is filtered through celite.The filtrate is concentrated and the residue is purified by silica gelchromatography (4:1, CH₂Cl₂/EtOAc) to yield crude product. Ethertrituration yields1-ethyl-2-(3-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (430 mg,72%) as a yellow-white solid.

The following compounds are prepared similarly as above, using othercommercially available iodides and bromides, or using iodides derivedfrom a one step amidation of p-iodophenylsulfonyl chloride: Compounds275, 276,277, 278, 331, 363, 364, 373, 374, 375, 474, 475, 678.

Example 1Ge Preparation of ethanesulfonic acid[4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide viaHeck Route (Compound 519)

Step A: A solution of 6-difluoromethoxy-1-ethyl-1H-indole (402.8 mg,2.04 mmol), ethanesulfonic acid (4-iodo-phenyl)-amide (712.1 mg, 2.29mmol), cesium carbonate (733.2 mg, 3.82 mmol), triphenylphosphine (33.1mg, 0.13 mmol) and palladium acetate (5.7 mg, 0.025 mmol) in DMF (5 ml)is heated to 135° C. for 48 h. The reaction mixture is diluted withwater and extracted with EtOAc (2×10 mL). The combined organic phasesare washed with brine, dried over MgSO₄, and then concentrated. Theresidue is purified via column chromatogrphy on silica gel (25 g) usingEtOAc/Hexanes (10-20%) as eluent to afford 298.2 mg (37.1% yield) ofethanesulfonic acid[4-(6-difluoromethoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-amide, compound 516,as a light brown solid.

Step B: Following the procedure 1A, step A, ethanesulfonic acid[4-(6-difluoromethoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-amide is convertedto ethanesulfonic acid[4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide,compound 519.

Following steps A and B above, the following compounds are prepared insimilar fashion: Compounds 343, 344,345,346, 409, 410, 411, 412, 413,414, 415, 416, 417, 418, 419, 463, 464, 465, 466, 467, 468, 469, 470,471, 472, 473, 515, 517, 518, 520, 521, 522, 523, 524, 575, 577, 579,580,611, 612, 613, 614

Example 1H Preparation of1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrile(Compound 67)

A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (150 mg,0.46 mmol), prepared as described in example 1Ga, step A,4-fluorophenylacetylene (80 mg, 0.0.69 mmol), bis(triphenylphosphine)palladium (II) dichloride (6 mg, 0.009 mmol) and CuI (4 mg, 0.018 mmol)is added to a sealable tube and alternately evacuated and flushed withN₂. To the tube is then added DMF (4 mL) and Et₃N (0.25 mL, 1.84 mmol)and the reaction is heated at 80° C. for 20 h and then cooled to roomtemperature. The reaction mixture is diluted with H₂O and extracted withEtOAc (2×). The combined organic phases are washed with H₂O (3×) andsaturated NaCl and then dried over MgSO4 and concentrated. The crudereaction mix is absorbed on silica gel (0.6 g) and chromatographed oversilica gel using EtOAc/hexanes (10-20%) as eluent to afford 120 mg (82%)of 1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrileas a yellow solid.

Utilizing essentially the same procedure described above andsubstituting different acetylene derivatives gives the followingcompounds: Compounds 64, 65, 66, 68, 69, 91, 92, 93, 94, 95, 96, 133,134, 135, 136, 137, 143, 144, 145, 146, 147, 148, 149, 150, 151, 158,159, 160, 161, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 184,185, 186, 187, 188, 196, 197, 198, 199, 200, 201, 202, 223, 230, 231,232, 233, 234, 235, 236, 237, 238.

Example 1I Preparation of1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-1H-indole (Compound28)

Step A: A solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00g, 5.00 mmol) in MeOH (10 mL) is treated with a 50% aqueous solution ofhydroxyamine (0.38 mL, 6.25 mmol) and heated at reflux for 18 h. Aftercooling to room temperature, the heterogeneous mixture is filtered toafford 525 mg of desired product as a tan solid. The filtrate isconcentrated to an oil, which is then dissolved in CH₂Cl₂ andchromatographed over silica gel using EtOAc/CH₂Cl₂ (15-50%) to afford anadditional 295 mg of product as a tan solid. Total yield of1-ethyl-N-hydroxy-6-methoxy-1H-indole-3-carboxamidine is 820 mg (70%).

Step B: The N-hydroxycarboxamidine above (50 mg, 0.21 mmol),polystyrene-diisopropylethylamine 165 mg, 3.90 mmol/g loading) andpropionyl chloride (0.03 mL, 0.32 mmol) in CH₂Cl₂ (10 mL) are placed ina tube and rotated for 22 h at room temperature. After this time,trisamine resin (77 mg, 2.71 mmol/g loading) is then added and the tuberotated for an additional 30 min at room temperature. Solids arefiltered and then the filtrate is concentrated and diluted with toluene(5 mL) and heated at 110° C. overnight. The crude reaction mixture isconcentrated and purified by chromatography (EtOAc/CH₂Cl₂, 2/98) toafford 27 mg (46%) of1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-1H-indole as a whitesolid.

The following compound is prepared utilizing the above procedure withsubstitution of the appropriate acyl halide: Compound 29.

Example 1J Preparation of1-ethyl-6-methoxy-3-(5-ethyl-[1,3,4]oxadiazol-2-yl)-1H-indole (Compound54)

Step A: A mixture of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00 g,5.00 mmol) in toluene (30 mL) is treated with triethylaminehydrochloride (1.03 g, 7.50 mmol) and sodium azide (0.49 g, 7.50 mmol)and is heated at reflux for 16 h. After cooling to room temperature, thereaction mixture is diluted with saturated NaHCO₃ and extracted withEtOAc. The organic layer is then washed with additional NaHCO₃ (2×). Thecombined aqueous phases are acidified to pH 2 with 6N HCl. The resultantthick precipitate is extracted with hot EtOAc (3×) and the combinedorganic phases are washed with saturated NaCl and dried and concentratedto give 0.55 g (45%) of 1-ethyl-6-methoxy-3-(1H-tetrazol-5-yl)-1H-indoleas a yellow solid.

Step B: A suspension of the tetrazole above (50 mg, 0.21 mmol) andpropionyl chloride (0.03 mL, 0.31 mmol) in dichloroethane (5 mL) isheated at reflux for 21 h. After cooling the reaction mixture to roomtemperature, polystyrene trisamine resin (70 mg, 3.4 meq/g) is added andthe reaction is rotated for 4 h at room temperature. After filtering offthe resin, and removal of the solvent, the crude product is absorbed onsilica gel and the product is isolated by silica gel chromatography(EtOAc/CH₂Cl₂, 5-10%) to afford 30 mg (53%) of1-ethyl-6-methoxy-3-(5-ethyl-[1,3,4]oxadiazol-2-yl)-1H-indole as a tansolid.

Example 1K Preparation of ethyl5-difluoromethoxy-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylate(Compound 49)

Freon-22 (HCF₂Cl) gas is bubbled into a solution of ethyl5-hydroxy-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylate (250 mg,0.77 mmol) in CH₂Cl₂ (5 mL) at 0° C. containing a small amount oftetrabutylammonium bromide as a phase transfer catalyst. A 50% solutionof NaOH is added dropwise at 0° C. After the addition, the mixture isstirred at 0° C. for 2 h. After the addition of H₂O, the organic phaseis separated and washed with brine and dried over Na₂SO₄. The solvent isthen concentrated and the residue is purified by column chromatographyover silica gel using EtOAc/petroleum ether (1/2) as eluent to yield thedesired product in 40% yield.

The following compounds are prepared utilizing the above procedure withsubstitution of the appropriate hydroxyindole: Compounds 18, 46, and 50.

Example 1L Preparation of1-[5-methoxy-1-(4-methoxyphenyl)-1-H-indol-3-yl]-ethanone (Compound 42)

5-Methoxy-1-(4-methoxyphenyl)-1-H-indole (50 mg, 0.2 mmol), prepared bythe method of example 1C, is dissolved in 1 mL of CH₂Cl₂ at 0° C.Et₂AlCl (300 μL, 1M in hexanes, 0.3 mmol) is then added. After stirringat 0° C. for 30 min, a solution of acetyl chloride (22 μL, 0.3 mmol) in1 mL of CH₂Cl_(2 i)s added dropwise. This is stirred at 0° C. for afurther 90 min. The reaction mixture is quenched with H₂O and isextracted with CH₂Cl₂ and concentrated in vacuo. Purification by columnchromatography on silica gel EtOAc/CH₂Cl₂ (5/95) yields the titlecompound as a white solid (42 mg, 71%).

Utilizing essentially the same procedure described above andsubstituting different acyl chlorides, the following compounds areprepared: Compounds 32, 33, 34, 37, 38, 39, 47, 48.

Example 1M Preparation of 1-ethyl-3-isoxazol-3-yl-6-methoxy-1-H-indole(Compound 57)

Step A: A mixture of 1-(1-ethyl-6-methoxy-1-H-indole-3-yl)ethanone (200mg, 0.92 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by theprocedure described in example 1L, hydroxyamine hydrochloride (128 mg,1.84 mmol), NaOAc (151 mg, 1.84 mmol) and EtOH (7 mL) is heated at 85°C. for 4 h. The reaction mixture is then partitioned between H₂O andEtOAc. The organic phase is dried and concentrated in vacuo.Purification by column chromatography using EtOAc/CH₂Cl₂ (1/9) yields1-(1-ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime as a white solid(189 mg, 92%).

Step B: 1-(1-Ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime (100 mg,0.43 mmol) is dissolved in THF (900 μL) at 0° C. n-BuLi (450 μL, 2.5 Min hexanes, 1.12 mol) is added dropwise, resulting in instantprecipitation of solids. DMF (70 μL, 0.9 mol) in 260 μL of THF is thenadded dropwise. This is stirred at 0° C. for 1 h, then at roomtemperature for 1 h. The reaction mixture is pipetted into a mixturecontaining 1 mL of H₂O, 1 mL of THF, and 100 μL of concentrated H₂SO₄.This mixture is heated at 75° C. for 1 h and then is partitioned betweenH₂O and EtOAc. The organic phase is dried and concentrated. Purificationby column chromatography (CH₂Cl₂) yields1-ethyl-3-isoxazol-3-yl-6-methoxy-1-H-indole product as a white solid(13 mg, 12%).

Example 1N Preparation of 1-ethyl-3-isoxazol-5-yl-6-methoxy-1H-indole(Compound 58)

1-(1-Ethyl-6-methoxy-1H-indol-3-yl)ethanone (100 mg, 0.46 mmol),prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described inexample 1L, is heated with 1.5 mL of dimethylformamide dimethylacetaland 100 μL of pyrrolidine at 110° C. overnight. The dimethylformamidedimethylacetal is then concentrated in vacuo. The residue is redissolvedin 1.25 mL of EtOH and 250 μL of H₂O, and is treated with hydroxyaminehydrochloride (66 mg, 0.95 mmol) and heated at 80° C. for 2 h.Partitioning between H₂O and EtOAc and drying and concentration of theorganic phase followed by purification by silica gel chromatography(EtOAc/CH₂Cl₂, 5/95) gives 1-ethyl-3-isoxazol-5-yl-6-methoxy-1H-indoleas a white solid (72 mg, 66%).

Utilizing essentially the same procedure described above, the followingcompound is prepared: Compound 60.

Example 1O Preparation of1-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)-1H-indole (Compound 59)

1-(1-Ethyl-6-methoxy-1H-indol-3-yl)-ethanone (100 mg, 0.46 mmol),prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described inexample 1L, is heated with 1.5 mL of dimethylformamide dimethyl acetaland 100 μL pyrrolidine at 110° C. overnight. The DMF dimethyl acetal isremoved in vacuo. The residue is redissolved in 3 mL of acetic acid,hydrazine hydrate (70 μL, 1.38 mmol) is added, and the mixture is heatedto 100° C. for 2 h. The acetic acid is removed in vacuo, and the residueis partitioned between EtOAc and saturated NaHCO₃. The organic phase isdried and concentrated and the product purified by silica gelchromatography (EtOAc/Hex, 1/1) to give 59 mg of1-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)-1H-indole (54%) as a colorlesssemisolid. Trituration in Et₂O gives a white crystalline powder.

The following compound is prepared utilizing the above procedure:Compound 61.

Example 1P Preparation of methyl1-ethyl-3-oxazol-5-yl-1H-indole-6-carboxylate (Compound 72)

Step A: 1-Ethyl-1H-indole-6-carboxylic acid methyl ester (900 mg, 4.45mmol) is dissolved in DMF (3.3 mL). This is added dropwise to anice-cold solution of POCl₃ (430 μL, 4.5 mmol) in DMF (1.5 mL). Thereaction mixture is stirred at room temperature for 90 minutes. Thereaction mixture is then treated with 6N NaOH (3.5 ml). The mixture isthen partitioned between H₂O and ethyl acetate. Purification by silicagel chromatography (5-10% EtOAc/CH₂Cl₂) yields1-ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (985 mg, 96%)as a white solid.

Step B: 1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (100mg, 0.42 mmol), TOSMIC (100 mg, 0.52 mmol), K₂CO₃ (178 mg, 1.29 mmol),and MeOH (800 μL) are heated at 80° C. overnight. The reaction mixtureis then partitioned between H₂O and ether. After drying andconcentrating the organic phase, the product is purified by silica gelchromatography (EtOAc/CH₂Cl₂, 10/90) to give methyl1-ethyl-3-oxazol-5-yl-1H-indole-6-carboxylate (26 mg, 23%) as anoff-white solid.

Example 1Q Preparation of methyl1-ethyl-3-oxazol-2-yl-1H-indole-6-carboxylate (Compound 75)

Step A: 1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (800mg, 3.5 mmol), prepared as shown in example 1P, step A, is dissolved inacetone (98 mL). A solution of KMnO₄ (655 mg, 4.15 mmol) in H₂O (31 mL)is added. The reaction mixture is stirred at room temperature for 90minutes. Another addition of KMnO₄ (108 mg) in H₂O (6 mL), followed bystirring for another 45 minutes is required to drive the reaction tocompletion. The reaction mixture is then quenched with 10% H₂O₂ (1.5mL). The mixture is filtered through celite. The filtrate is strippeddown under vacuum to roughly ⅓ of the volume. The residue is acidifiedwith 6N HCl, and is extracted into ethyl acetate. The solids isolatedfrom the ethyl acetate layer are triturated with acetone to yield1-ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (696 mg, 79%) asa light orange solid.

Step B: 1-Ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (600 mg,2.43 mmol) is suspended in a solution of CH₂Cl₂ (27 ml) and DMF (20 μL).Oxalyl chloride (470 μL, 5.38 mmol) is added, and the reaction mixtureis stirred for 1 hour at room temperature. This mixture is then slowlypoured into a rapidly stirring solution of concentrated NH₄OH (10 mL).This is then partitioned in H₂O and EtOAc. The residue from the ethylacetate layer is triturated with acetone to yield6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide (511 mg, 85%) as awhite solid.

Step C: A mixture of 150 mg (0.61 mmol) of6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide in diglyme (3.6 mL),and bromoacetaldehyde dimethyl acetal (430 μL, 3.7 mmol) is heated at125° C. for 2 h. The reaction mixture is cooled and partitioned in H₂Oand EtOAc. The organic phase is dried and concentrated and the productis purified by silica gel chromatography (EtOAc/CH₂Cl₂ 5-10%). Theproduct containing fractions are combined and concentrated and the solidis triturated with hexanes to yield methyl1-ethyl-3-oxazol-2-yl-1H-indole-6-carboxylate (75 mg, 46%) as a yellowsolid.

Example 1R Preparation of 1-ethyl-6-methoxy-3-thiazol-2-yl-1H-indole(Compound 73)

Step A: 1-Ethyl-6-methoxy-1H-indole (900 mg, 5.14 mmol) is dissolved inDMF (1.5 mL). This is added dropwise to an ice-cold solution of POCl₃(500 μL, 5.2 mmol) in DMF (1.75 ml). After stirring at room temperaturefor 90 minutes, the reaction mixture is re-cooled in an ice bath and isslowly quenched with 6N NaOH (4 mL). The reaction mixture is partitionedbetween EtOAc and H₂O. Purification by silica gel chromatography(EtOAc/CH₂Cl₂, 5/95) yields 1-ethyl-6-methoxy-1H-indole-3-carbaldehyde(849 mg, 81%) as a yellow solid.

Step B: 1-Ethyl-6-methoxy-1H-indole-3-carbaldehyde (600 mg, 2.95 mmol)is dissolved in acetone (85 mL). A solution of KMnO₄ (450 mg, 2.85 mmol)in H₂O (28 mL) is added. This is stirred at room temperature for 5hours. Another solution of KMnO₄ (450 mg, 2.85 mmol) in H₂O (25 mL) isthen added. After stirring for another hour at room temperature, thereaction is complete. The reaction mixture is quenched with 10% H₂O₂(1.5 mL), and is then filtered through celite. The filtrate is strippeddown under vacuum to roughly ⅓ of the volume. The residue is acidifiedwith 6N HCl, and is extracted into ethyl acetate. Purification by silicagel column (hexanes/acetone/acetic acid, 70/30/1) yields crude product.Trituration with ether yields pure1-ethyl-6-methoxy-1H-indole-3-carboxylic acid (365 mg, 56%) as a yellowsolid.

Step C: 1-Ethyl-6-methoxy-1H-indole-3-carboxylic acid (250 mg, 1.14mmol) is suspended in a solution of CH₂Cl₂ (12.5 mL) and DMF (10 μL).Oxalyl chloride (230 μL, 2.64 mmol) is added, and the reaction mixtureis stirred for 1 hour at room temperature. This mixture is then slowlypoured into a rapidly stirring solution of concentrated NH₄OH (5 mL).This is then partitioned in H₂O and EtOAc. The residue from the ethylacetate layer is triturated with acetone to yield1-ethyl-6-methoxy-1H-indole-3-carboxamide (134 mg, 54%) as a whitesolid.

Step D: 1-Ethyl-6-methoxy-1H-indole-3-carboxamide (120 mg, 0.55 mmol),Lawesson's reagent (240 mg, 0.6 mmol), and toluene (2 mL) are heated at90° C. for 90 min. The reaction mixture is concentrated and purified bysilica gel chromatography (EtOAc/CH₂Cl₂, 1/9) to yield1-ethyl-6-methoxy-1H-indole-3-thiocarboxamide as a yellow solid (92 mg,71%).

Step E: 1-Ethyl-6-methoxy-1H-indole-3-thiocarboxamide (83 mg, 0.36mmol), glyme (3.6 mL) and bromoacetaldehyde dimethyl acetal (220 μL,1.86 mmol) are heated at 80° C. for 16 h. More bromoacetaldehydedimethyl acetal (250 μL) is added. This is heated at 80° C. for 2 h.Addition of 250 μL more bromoacetaldehyde dimethyl acetal is followed byheating for another 2 hours. The reaction mixture is cooled to roomtemperature, absorbed onto silica and purified by silica gelchromatography (hexanes/EtOAc, 7/3) to afford1-ethyl-6-methoxy-3-thiazol-2-yl-1H-indole as a brown oil (44 mg, 47%).

The following compounds are prepared following the procedure describedabove: Compounds 78, 101, 104, 105 and 106.

Example 1S Preparation of1-ethyl-6-methoxy-2-phenoxymethyl-1H-indole-3-carbonitrile (Compound 99)

Step A: To a suspension of LiAlH₄ (7.6 g, 0.2 mol) in dioxane (100 mL)is added dropwise a solution of methyl 6-methoxy-1H-indole-2-carboxylate(8.2 g, 0.04 mol) in dioxane (50 mL) at 0° C. After the addition, themixture is stirred at room temperature for 1 h and then heated at refluxfor 5 h. After cooling to 0° C., the reaction is quenched by water(dropwise) and then 15% aqueous NaOH. After stirring at room temperaturefor 1 h, the mixture is filtered through Celite. The solid is washedwith a large amount of EtOAc. The solvent is washed with brine, driedover Na₂SO₄ and evaporated under vacuum. The residue is purified byflash column chromatography on silica gel using EtOAc/petroleum ether(1/5) as eluent to yield 61% of 6-methoxy-2-methyl-1H-indole.

Step B: To a solution of 6-methoxy-2-methyl-1H-indole (3.9 g, 24 mmol)in acetonitrile (200 mL) and DMF (20 mL) is added dropwise a solution ofClSO₂NCO (4 mL, 1.3 eq.) in acetonitrile (31 mL) at 0° C. After theaddition, the mixture is stirred at room temperature for 3 h. Then it ispoured into ice water and saturated NaHCO₃ is added to it until itbecomes basic. The aqueous phase is extracted with CH₂Cl₂ and thenevaporated. The residue is purified with flash column chromatography onsilica gel using EtOAc/petroleum ether (1/5) as eluent to yield 81% of6-methoxy-2-methyl-1H-indole-3-carbonitrile.

Step C: To a suspension of NaH (0.6 g, 2 eq.) in DMF (7 mL) is added asolution of 6-methoxy-2-methyl-1H-indole-3-carbonitrile (1.3 g, 7.0mmol) in DMF (8 mL) followed by ethyl iodide (1.2 mL, 2 eq.) at 0° C.After stirring for 1 h, the mixture is poured into ice water and thenextracted with CH₂Cl₂. The organic layer is washed with brine and driedwith Na₂SO₄. The solvent is evaporated under vacuum and purified withflash column chromatography on silica gel using EtOAc/petroleum ether(1/5) as eluent to yield 92% of1-ethyl-6-methoxy-2-methyl-1H-indole-3-carbonitrile.

Step D: To a solution of1-ethyl-6-methoxy-2-methyl-1H-indole-3-carbonitrile (1.38 g, 6.45 mmol)in benzene (130 mL) is added benzoyl peroxide (226 mg) and NBS (1.21 g,1.05 eq.). Then the mixture is heated to reflux for 3 h. After coolingand filtering, the filtrate is concentrated under vacuum. The crude2-bromomethyl-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.6 g, 86%) isused without further purification.

Step E: To a solution of NaH (44 mg, 4 eq.) in DMF (0.5 mL) is added2-bromomethyl-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (80 mg, 0.274mmol) and phenol (2 eq.). After stirring for 20 h, the mixture is pouredinto ice water and extracted with CH₂Cl₂. The organic layer is washedwith brine and dried with Na₂SO₄. The solvent is evaporated under vacuumand purified with flash column chromatography on silica gel usingEtOAc/petroleum ether (1/5) as eluent to yield1-ethyl-6-methoxy-2-phenoxymethyl-1H-indole-3-carbonitrile, compound 99.

Example 1T Preparation of 6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile(Compound 7)

Step A: A solution of 2-fluoro-5-nitroaniline (11.7 g, 74.9 mmol) indimethylformamide (120 mL) is treated with malononitrile (5.28 g, 80.0mmol) and potassium carbonate (11.05 g, 80.0 mmol) (Modification ofChem. Heterocyclic Cpd. Engl. Trans., 9, 37 (2001)). The resultingheterogeneous mixture is heated to gentle reflux for 3 h, then cooledand poured into water (500 mL). The resulting precipitate is collectedby filtration and taken up into ethyl acetate (300 mL). This solution isdried over Na₂SO₄, filtered and partially evaporated to give aprecipitate, which is collected by filtration. Further evaporation andfiltration give a second crop. The two crops are combined and driedunder vacuum to give 2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile(7.90 g, 52%) as an orange powder.

Step B: A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile (362 mg,1.79 mmol) in acetic acid (5 mL) is treated with2,5-dimethoxytetrahydrofuran (0.30 mL, 2.27 mmol), and the solution isheated to reflux for 14 h. After cooling to ambient temperature, thesolution is poured into water (100 mL), and solid sodium bicarbonate isadded until CO₂ evolution ceased. The mixture is extracted with EtOAc(2×100 mL), and the extracts are washed with saturated brine, combined,dried over MgSO₄, filtered and concentrated. The residual material isseparated by silica gel chromatography (EtOAc/hexanes, 1/4) to afford6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile, compound 5, as a yellowsolid (232 mg, 51%).

Example 1U Preparation ofN-(3-cyano-1-ethyl-6-nitro-1H-indol-2-yl)acetamide (Compound 25)

Step A: Sodium hydride (42 mg, 1.05 mmol, 60% w/w suspension in mineraloil) is washed with hexane and taken up in dimethylsulfoxide (1 mL). Asolution of 2-amino-6-nitro-1H-indole-3-carbonitrile (prepared inprocedure 1T) in dimethylsulfoxide (1 mL) is added by syringe, and theresulting mixture is stirred for 20 min. Then, iodoethane (77 μL, 0.96mmol) is added by syringe, and the mixture is stirred for 14 h. Thereaction is then poured into EtOAc (50 mL), and this solution is washedwith water (3×50 mL) and saturated brine (40 mL). The aqueous phases areback-extracted with EtOAc, and the organic extracts are combined, driedover Na₂SO₄, filtered and evaporated. The residual material is separatedby column chromatography over silica gel (EtOAc/hexanes, 1/1) to affordfirst a small amount of a dialkylated analog, then the desired compound,2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (114 mg, 52%), andfinally unreacted starting material. The desired product is isolated asan orange powder.

Step B: Sodium hydride (44 mg, 1.10 mmol, 60% w/w in mineral oil) iswashed with hexanes and suspended in 1,4-dioxane (3 mL). A solution of2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (120 mg, 0.521 mmol),prepared in step B, above, in dioxane (2 mL) is added, and the resultingmixture is allowed to stir for 30 min. Then, acetyl chloride (45 μL,0.63 mmol) is added by syringe, and the solution is stirred for anadditional 12 h. The reaction is partitioned between water and EtOAc (20mL each), and the organic phase is washed with brine. The aqueous phasesare back-extracted in sequence with ethyl acetate, and the organicextracts are combined, dried over MgSO₄, filtered and evaporated. Theresulting solid is triturated with Et₂O, collected by filtration anddried under vacuum to affordN-(3-cyano-1-ethyl-6-nitro-1H-indol-2-yl)-acetamide (100 mg, 71%),compound 25, as an off-white powder.

Using this procedure and substituting the appropriate acid chlorides orchloroformates gives the following compounds: Compounds 23, 26, 35, 36,203, 204, 214, 215, 216.

Example 1V Preparation of N-ethyl-3-phenyl-5-nitroindole (Compound 41)

Step A: To a solution of 5-nitroindole (5.00 g, 30.8 mmol) in pyridine(200 mL) at −4° C. is added a solution of pyridinium bromide perbromide(10.99 g, 34.3 mmol) in pyridine (200 mL) dropwise under nitrogen withstirring. After complete addition, the reaction mixture is stirred for 5min at 0° C. The reaction mixture is diluted in 0° C. water (200 mL) andextracted with 200 mL of Et₂O. The organic layer is washed with 6 M HCl(300 mL), 5% NaHCO₃ (300 mL), and brine (300 mL). The organic phase isdried over MgSO₄ and solvent is removed to give 3-bromo-5-nitroindole asa yellow powder, 80% pure with 20% 5-nitroindole (6.80 g, 74% yield).

Step B: A solution of 3-bromo-5-nitroindole from above (625 mg, 2.1mmol), phenylboronic acid (381 mg, 3.13 mmol), triphenylphosphine (109.3mg, 0.417 mmol) in dimethoxyethane (4.16 mL) is degassed. To thismixture 2N sodium carbonate (6.25 mL) is added, and the reaction mixtureis degassed again. To the reaction is added palladium (II) acetate (23.4mg, 0.104 mmol), and the reaction is refluxed under dry nitrogen withstirring for 8 hours. The reaction mixture is then diluted with 1 M HCl(100 mL), and extracted with ethyl acetate (100 mL). The organic phaseis washed with water (100 mL), and brine (100 mL). The organic phase isdried over MgSO₄ and concentrated in vacuo. The crude product ispurified by chromatography over silica gel (EtOAc/hexanes, 10/90) toafford 3-phenyl-5-nitroindole as an orange powder (45 mg, 9% yield).

Step C: To a mixture of 60% NaH in mineral oil (8.7 mg, 0.630 mmol) andDMF (1.0 mL) is added dropwise a solution of 3-phenyl-5-nitroindole(40.0 mg, 2.1 mmol) in DMF (0.75 mL). The reaction mixture is stirredfor 20 min at 0° C. under N₂. Ethyl iodide (14.8 μL, 0.185 mmol) isadded dropwise and the reaction mixture is stirred for an additional 3hours. The reaction mixture is diluted with water (250 mL), andextracted with EtOAc (30 mL). The organic phase is washed with water(250 mL) and is then dried over MgSO₄ and the solvent is removed invacuo. The desired N-ethyl-3-phenyl-5-nitroindole is obtained as ayellow powder (40.0 mg, 89.5% yield).

In similar fashion the following compound is prepared: Compound 40.

Example 1W Preparation of[3-Cyano-1-(4-methoxyphenyl)-1H-indol-6-yl]-carbamic acid propyl ester(Compound 97)

6-Amino-1-(4-methoxyphenyl)-1H-indole-3-carbonitrile (30 mg, 0.12 mmol),is suspended in EtOH (300 μL). Propyl chloroformate (168 μL, 1.5 mmol)is added, and this mixture is stirred at room temperature overnight. Theaddition of triethylamine (300 μL), followed by another hour of stirringat room temperature, completes the reaction. This reaction mixture isloaded directly onto a silica column, and is eluted with CH₂Cl₂. Anothersilica column (3/2, ether/hexanes) is needed to fully purify theproduct, [3-cyano-1-(4-methoxy-phenyl)-1H-indol-6-yl]-carbamic acidpropyl ester (19 mg, 45%), as a white solid.

Example 1X Preparation ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-methanesulfonamide(Compound 130)

2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50mg, 0.16 mmol), prepared as described by the method of Example 1H, isdissolved in pyridine (550 μL) at room temperature. Methanesulfonylchloride (17 μL, 0.21 mmol) is added dropwise. This is stirred overnightat room temperature. The reaction mixture is then diluted in ethylacetate and is washed with aqueous HCl, followed by brine. The organiclayer is dried and concentrated. Purification by silica gelchromatography (9/1, CH₂Cl₂/EtOAc) yieldsN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-methanesulfonamide(58 mg, 92%) as an off-white solid.

The following compounds are made using the procedure shown above, bysubstituting the appropriate aminophenylethynyl indoles and sulfonylchlorides: Compounds 131, 132, 208, 209, and 210.

Example 1Y Preparation ofN-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-methanesulfonamide(Compound 129)

A solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg,0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL)is cooled to 0° C. and treated with triethylamine (0.04 mL, 0.31 mmol)and methanesulfonylchloride (0.02 mL, 0.29 mmol) and stirred, warming toroom temperature overnight. The reaction mixture is then diluted withH₂O and extracted with ethyl acetate (3×). The organic phase is washedwith H₂O and saturated NaCl, dried and concentrated and purified byflash chromatography using EtOAc/hexanes (30-50%) to afford 60 mg (68%)ofN-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-methanesulfonamideas a tan solid.

Using essentially the same procedure as above and substituting theappropriate aminophenylindole and sulfonyl chloride or carrying out thereaction in pyridine as both base and solvent gives the followingcompounds: Compounds 83, 85, 86, 87, 88, 243, 251, 252, 272, 273, 287,289, 365, 366, 367, 368, 369, 370, 371, 394, 439, 440, 448, 449, 451,452, 477, 487, 488, 495, 505, 510, 548, 549, 550, 551, 552, 562, 563,598, 599, 601, 602, 608, 609, 610, 615, 616, 617, 621, 622, 623, 629,630, 631, 639, 655, 657, 658, 662, 669, 670, 671, 674, 675, 701, 702,703, 706, 707, 708, 709, 710, 711, 713, 715, 720, 789, 790, 791, 850,851, 867, 868, 890, 891, 912, 919, 920, 921, 922, 923, 924, 932, 933,934, 935, 941, 953, 968, 982, 988, 990, 995, 996, 997, 998, 1035, 1038,1041, 1103, 1105,1115, 1116, 1117, 1123, 1140, 1141, 1155, 1160, 1161,1170, 1175, 1181, 1182, 1188, 1189, 1228, 1229, 1230, 1231, 1280.

Example 1Za Preparation ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamide(Compound 138)

2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (95mg, 0.29 mmol), prepared as described in Example 1H, is dissolved in THF(1.4 mL). Triethylamine (84 μL, 0.6 mmol) is added, followed by dropwiseaddition of acetyl chloride (44 μL, 0.5 mmol). This is stirred at roomtemperature for 1 h. The reaction mixture is partitioned between H₂O andEtOAc. The organic layer is dried and concentrated. Purification bysilica chromatography (9/1, CH₂Cl₂/EtOAc) yieldsN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamide(103 mg, 96%) as a yellow solid.

The following compounds are prepared by the procedure shown above,substituting the appropriate aminophenylethynyl indoles and acidchlorides: Compounds 82, 139, 152, 153, 162, 163, 165, 167,205, 206,207,211,212, 213, 219, 224, 225, 228.

Example 1Zb Preparation ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-formamide(Compound 241)

Acetic anhydride (2.5 mL) and 98% formic acid (1.0 mL) are heated at 65°C. for 1 hour. This is cooled to 0° C.2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100mg, 0.32 mmol), prepared as in example 1H, is taken up in THF (1.2 mL)and added to the formic acetic anhydride mixture. This is stirred at 0°C. for 30 minutes. The reaction mixture is then partitioned between H₂Oand EtOAc. The EtOAc layer is washed with saturated NaHCO₃, followed bysaturated brine. The organic layer is dried and concentrated.Purification by silica gel chromatography (4/1, CH₂Cl₂/EtOAc) yields ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-formamide(105 mg, 96%) as a yellow solid.

The following compound is prepared similarly as described above:Compound 218.

Example 1AA Preparation ofN-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-acetamide(Compound 128)

A solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg,0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL)is cooled to 0° C. and treated with triethylamine (0.04 mL, 0.31 mmol)and acetyl chloride (0.02 mL, 0.29 mmol) and stirred, warming to roomtemperature overnight. The reaction mixture is then diluted with H₂O andextracted with ethyl acetate (3×). The organic phase is washed with H₂Oand saturated NaCl, dried and concentrated and purified by flashchromatography using EtOAc/hexanes (30-50%) to afford 57 mg (71%) ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]acetamide as a tansolid.

Using essentially the same procedure as above and substitutingappropriate aminophenyl indoles and the acid chlorides, the followingcompounds are prepared: Compounds 81, 242, 244, 324, 325, 326, 327, 328,329, 330, 383, 420, 421, 422, 423, 424, 425, 544, 558, 559, 560, 561,565, 566 567, 644, 645, 646, 755, 756, 757, 759, 760, 761, 762, 763,764, 765, 766, 798, 799, 801, 802, 803,804, 854, 855, 856, 857, 858,859, 895, 896, 897, 898, 899, 900, 901, 913, 914, 915, 916, 983.

Example 1AB Preparation of1-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)phenyl]-3-ethylurea (Compound 220)

2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100mg, 0.32 mmol), prepared as described in Example 1H, is dissolved inpyridine (670 μL). Ethyl isocyanate (62 μL, 0.75 mmol) is added. Thereaction mixture is then heated at 100° C. for 2 h. The mixture is thendiluted in EtOAc, and is washed with aqueous HCl, followed by brine. Theorganic layer is dried and concentrated. Purification by silicachromatography (4/1, CH₂Cl₂/EtOAc), followed by trituration withhexanes/acetone (1/1), yields1-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-3-ethylurea (44 mg, 36%) as a white solid.

Example 1AC Preparation of1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea(Compound 156)

2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100mg, 0.32 mmol), prepared as described in Example 1H, is suspended intoluene (600 μL). 2-Chloroethyl isocyanate (32 μL, 0.37 mmol) is added,and the mixture is heated at 100° C. for 5 h. The reaction mixture isthen cooled, diluted in acetone, and absorbed onto silica. Purificationby column chromatography (5-10% EtOAc in CH₂Cl₂) yields1-(2-chloro-ethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea(73 mg, 54%) as a yellow solid.

The following compound is prepared using the procedure above: Compound221.

Example 1AD Preparation of Ethanesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]methyl amide(Compound 157)

N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)phenyl]ethanesulfonamide(70 mg, 0.17 mmol), prepared as in Example 1X, is combined with K₂CO₃(49 mg, 0.35 mmol), and DMF (1.0 mL). Iodomethane (16 μL, 0.26 mmol) isadded, and the mixture is stirred at room temperature for 1 hour. Thereaction mixture is then diluted in EtOAc, and is washed with H₂O andthen brine. The organic layer is dried and concentrated. Purification bysilica chromatography (95/5, CH₂Cl₂/EtOAc) yields a light tan solid.Trituration gives ethanesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]methyl amide(61 mg, 85%) as an orange-white solid.

The following compounds are prepared using the procedure above,substituting the appropriate sulfonamide: Compound 182, 652, 840.

Example 1AE Preparation of1-ethyl-5-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile(Compound 245)

Step A: Methyl 4-(3-cyano-1-ethyl-5-methoxy-1H-indol-2-yl)-benzoate (350mg, 1.05 mmol), prepared as described in Example 1Ga step B, is combinedwith NaOH (40 mg, 1 mmol), H₂O (0.8 mL), and THF (3.4 mL) and is heatedat 80° C. for 1 hour. The reaction mixture is diluted in H₂O and is thenether-washed. The aqueous layer is acidified with aqueous HCl, and isextracted into EtOAc. The organic layer is dried and concentrated toyield 4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (311 mg,92%) as a pure white solid.

Step B: 4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (50 mg,0.16 mmol) is suspended in CH₂Cl₂ (2.2 mL) and catalytic DMF (2 μL).Oxalyl chloride (22 μL, 0.25 mmol) is added. The reaction mixture isstirred at room temperature for 1 hour, at which time full dissolutionoccurred. This reaction mixture is pipetted dropwise into a vigorouslystirring solution of morpholine (1.0 mL) in CH₂Cl₂ (5 ml). Afteraddition is complete, the reaction mixture is washed with aqueous HClsolution. The organic layer is dried and concentrated. Purification bysilica column (1:1 CH₂Cl₂/EtOAc) yields1-ethyl-6-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile(56 mg, 90%) as a white solid.

The following compounds are prepared similarly as described above:Compounds 113, 114, 246, 270, 271 290, 291, 292, 323, 377, 378, 379,380, 381, 382, 384, 385, 386, 387, 388, 389, 390, 391, 392, 432, 433,564, 568, 569, 570, 571, 572, 573, 647, 648, 853, 860, 861, 862.

Example 1AF Preparation of cyclopropanecarboxylic acid[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-ylethynyl)-phenyl]amide(Compound 194)

Cyclopropanecarboxylic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-amide (60mg, 0.16 mmol), prepared as described in Example 1Za, is stirred in BBr₃(800 μL, 1M in CH₂Cl₂, 0.8 mmol) at room temperature for 1 hour. Thereaction mixture is quenched with H₂O, and is extracted with CH₂Cl₂. Theorganic layer is dried and concentrated. Purification by silicachromatography (EtOAC) gives impure product. This crude product istriturated with 1/1 hexanes/acetone to yield cyclopropanecarboxylic acid[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-ylethynyl)-phenyl]-amide (32mg, 54%) as an off-white solid.

The following compounds are prepared using the procedure above,substituting the appropriate sulfonamides (from Example 1X) or amides(from Example 1Z): Compounds 164, 168, 183, 193, 195.

Example 1AG Preparation of1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile(Compound 166)

1-(2-Chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea(55 mg, 0.13 mmol), prepared as in Example 1AC, is combined with K₂CO₃(50 mg, 0.36 mmol) and DMF (550 μL). This mixture is stirred at roomtemperature for 3 hours. The reaction mixture is diluted in EtOAc, andis washed with H₂O, and then with brine. The organic layer is dried andconcentrated. Purification by silica chromatography (10-50%,EtOAc/CH₂Cl₂) yields1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile(47 mg, 94%) as a white solid.

The following compound is prepared using the above procedure,substituting the appropriate urea: Compound 222.

Example 1AH Preparation ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-dimethylphosphinicamide (Compound 227)

2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100mg, 0.32 mmol), prepared as described in Example 1H, is dissolved inpyridine (300 μL) at 0° C. Dimethylphosphinic chloride (60 mg, 0.53mmol) in THF (300 μL) is added. The reaction is stirred at roomtemperature for 2 hours. The reaction mixture is diluted in EtOAc, andis washed with aqueous HCl followed by brine. The organic layer is driedand concentrated. Purification by silica chromatography (acetone) yieldsN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-dimethylphosphinicamide (65 mg, 52%), compound 227, as a pure white solid. The silicacolumn is then flushed with 9/1 CH₂Cl₂/MeOH to yield 9 mg ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-bis-(dimethylphosphinic)amide as a by-product.

Example 1AI Preparation of1-ethyl-6-methoxy-3-[5-(4-methoxyphenyl)-isoxazol-3-yl]-1H-indole(Compound 116)

Step A: A mixture of 1-ethyl-6-methoxy-1H-indole-3-carbaldehyde oxime(0.20 g, 0.92 mmol), prepared from the aldehyde precursor in example 1R,in dichloroethane (3 mL) is treated with N-chlorosuccinimide (0.12 g,0.92 mmol) and pyridine (0.04 mL, 0.46 mmol) and stirred at roomtemperature for 1 h. The reaction mixture is then poured into H₂O andacidified with 1N HCl until the pH is 2. The mixture is extracted withEtOAc and the organic phases are washed with H₂O and saturated NaCl anddried and concentrated to a mixture of chlorooximes, which are used inthe next step without further purification.

Step B: The mixture of chlorooximes prepared above is dissolved inCH₂Cl₂ (5 mL) and to this is added 4-methoxyphenylacetylene (0.24 g,1.84 mmol) and triethylamine (0.25 mL, 1.84 mmol) at 0° C. and thereaction is then stirred overnight warming to room temperature. Thereaction is then diluted with H₂O and extracted with EtOAc (3×). Theorganic phases are washed with H₂O and saturated NaCl and dried andconcentrated. Chromatography over silica gel (EtOAc/hexanes, 10-20%)gives 76 mg (24%) of1-ethyl-6-methoxy-3-[5-(4-methoxy-phenyl)-isoxazol-3-yl]-1H-indole as atan solid.

Example 1AJ Preparation of[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethylester (Compound 121)

A biphasic mixture of2-(4-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg,0.24 mmol), prepared as described in example 1Ga step B, and ethylchloroformate (0.03 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO₃(3 mL) is prepared at 0° C. and then allowed to warm to room temperatureand stirred for 24 h. The reaction is then diluted with H₂O andextracted with EtOAc (2×). The organic phases are washed with H₂O andsaturated NaCl and then dried and concentrated. Flash chromatography(EtOAc/hexanes 20-40%) gives 48 mg (55%) of[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethylester as an off-white solid.

The following compounds are prepared in similar fashion: Compound 122,293, 294, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307,308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321,349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 372,434, 435, 450, 453, 454, 455, 457, 485, 486, 489, 490, 500, 501, 502,503, 506, 507, 508, 509, 545, 546, 547, 553, 554, 555, 556, 557, 581,582, 583, 584, 585, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594,595, 596, 597, 603, 604, 605, 606, 607, 618, 619, 624, 625, 637, 640,641, 664, 665, 676, 677, 721, 722, 723, 734, 735, 736, 737, 738, 739,744, 745, 746, 747, 787, 788, 792, 793, 794, 795, 796, 797, 819, 822,823, 824, 825, 826, 849, 925, 926, 945, 946, 947, 948, 949, 950, 951,970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 981, 984, 985, 986,991, 992, 993, 1015, 1020, 1021, 1022, 1029, 1030, 1031, 1032, 1033,1034, 1037, 1040, 1042, 1044, 1055, 1056, 1057, 1058, 1059, 1062, 1063,1064, 1065. 1071, 1073, 1074, 1075, 1077, 1078, 10791107, 1109, 1111,1112, 1113, 1114, 1122, 1127, 1128, 1129, 1145, 1148, 1149, 1150, 1151,1152, 1153, 1154, 1169, 1174, 1176, 1177, 1178, 1179, 1180, 1186, 1193,1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205,1206, 1207, 1211, 1222, 1232, 1233, 1300, 1302.

Example 1AK Preparation of1-ethyl-5-thiophen-3-yl-1H-indole-3-carbonitrile (Compound 141)

A tube is charged with a mixture of5-bromo-1-ethyl-1H-indole-3-carbonitrile (100 mg, 0.40 mmol),thiophene-3-boronic acid (72 mg, 0.56 mmol), PdCl₂(PPh₃)₂ (11 mg, 0.016mmol) and CsF (152 mg, 1 mmol) and then alternately evacuated and filledwith nitrogen (3×) and diluted with dimethoxyethane (3 mL) and thenheated to 90° C. for 19 h. After cooling, the crude reaction mixture isdiluted with saturated NaHCO₃ and extracted with EtOAc (2×). Thecombined organic phases are washed with saturated NaCl and dried andconcentrated. Flash chromatography over silica gel (CH₂Cl₂/hexanes,40/60) gives 25 mg (25%) of1-ethyl-5-thiophen-3-yl-1H-indole-3-carbonitrile as a white solid.

The following compounds are prepared in similar fashion: Compounds 140and 142.

Example 1AL Preparation ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-methylmethanesulfonamide (Compound 180)

A solution ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide(130 mg, 0.35 mmol), prepared as in Example 1Y, in DMF (10 mL) istreated with NaH (21 mg, 0.53 mmol), and stirred at room temperature for10 min. Iodomethane (0.03 mL, 0.53 mmol) is added, and the mixture isstirred at room temperature for 18 h. The reaction mixture is thendiluted with H₂O, and extracted with EtOAc (2×). The organic phases arewashed with H₂O and saturated NaCl and then dried and concentrated.Purification by flash chromatography over silica gel (EtOAc/CH₂Cl₂,0-1%) gives 60 mg (45%) ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-methylmethanesulfonamide as a white solid.

In similar fashion the following compounds are prepared: Compounds 181,642, 643, 672, 673, 816, 852, 1002, 1003, 1004, 1005, 1006, 1007.

Example 1AM Preparation ofN-[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-methanesulfonamide(Compound 189)

A solution ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide(85 mg, 0.23 mmol) in CH₂Cl₂ (2 mL) is cooled to −5° C. A solution ofboron tribromide (1.15 mL, 1.15 mmol, 1M solution in CH₂Cl₂) is addedand the reaction mixture is allowed to warm to 10° C. over 4 h. Thereaction mixture is poured into H₂O and extracted with EtOAc (3×). Thecombined organic phases are washed with H₂O and saturated NaCl and driedand concentrated. Chromatography over silica gel (EtOAc/CH₂Cl₂, 5-10%)gives 18 mg (22%) ofN-[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]methanesulfonamideas a tan solid.

The following compounds are made similarly: Compounds 190, 191, 192.

Example 1AN Preparation of methyl3-[5-(3-cyano-6-methoxy-1H-indol-2-yl)-[1,2,4]oxadiazol-3-yl]benzoate(Compound 226)

Step A: To a mixture of 6-methoxy-1H-indole-3-carbonitrile (5.88 g, 40mmol), prepared as described in the previous examples, and (Boc)₂O (9.59g, 44.0 mmol) in DCM (50 mL) is added DMAP (0.10 g, 0.8 mmol). Themixture is stirred at room temperature for 48 h, then treated with water(30 mL) and dried over anhydrous Na₂SO₄. The crude product ischromatographed over silica gel (hexanes/EtOAc, 7/1) to furnish thedesired intermediate, 3-cyano-6-methoxyindole-1-carboxylic acidtert-butyl ester (8.48 g, 86%).

Step B: The above intermediate (2.72 g, 10.0 mmol) is dissolved inanhydrous THF (20 mL), and cooled at −78° C., followed by the additionof LDA (1.5 M monoTHF in cyclohexane, 10.0 mL, 15 mmol). After stirringfor 45 min, CO₂ gas is introduced for 2 h. The mixture is then broughtto room temperature and the solvent is removed in vacuo, and the residueis treated with water and acidified to pH=2 with 6 N HCl. Theprecipitate is collected and washed with water and dried to provide theacid intermediate, 3-cyano-6-methoxy-indole-1,2-dicarboxylic acid1-tert-butyl ester (2.40 g, 73%).

Step C: To a solution of 3-cyano-6-methoxyindole-1,2-dicarboxylic acid1-tert-butyl ester (474 mg, 1.5 mmol) prepared above, and HOBt (200 mg,1.5 mmol) in DCE/DMF (10 mL/1 mL), is added DCC (310 mg, 1.5 mmol),followed by 3-(N-hydroxycarbamimidoyl)benzoic acid methyl ester (291 mg,1.5 mmol). The mixture is stirred at room temperature for 2 h andfiltered. The filtrate is collected and the solvent is replaced withchlorobenzene, followed by the heating at 150° C. for 48 h. Aftercooling to room temperature, the solvent is removed in vacuo and theresidue is chromatographed (silica gel, CH₂Cl₂/EtOAc, 8/2) to furnishthe intermediate,3-cyano-6-methoxy-2-[3-(3-methoxycarbonylphenyl)-[1,2,4]oxadiazol-5-yl]-indole-1-carboxylicacid tert-butyl ester, which is treated with 50% TFA in DCM (10.0 mL) atroom temperature for 1 h. After removal of the volatiles in vacuo, theresidue is suspended in water and neutralized with K₂CO₃ to provide thedesired product, methyl3-[5-(3-cyano-6-methoxy-1H-indol-2-yl-)[1,2,4]oxadiazol-3-yl]benzoate,compound 226 (350 mg, 62%).

Example 1AO Preparation of1-ethyl-2-(4-methanesulfonylphenyl)-6-methoxy-1H-indole-3-carbonitrile(Compound 265)

A solution of1-ethyl-6-methoxy-2-(4-methylsulfanylphenyl)-1H-indole-3-carbonitrile(0.12 g, 0.37 mmol) in CH₂Cl₂ (5 mL) is treated with m-chloroperbenzoicacid (Aldrich, <77%, 0.26 g,) in one portion and the reaction is stirredfor 10 h at room temperature. The reaction is then diluted with H₂O andsaturated NaHCO₃ and extracted twice with EtOAc. The organic phases arewashed with NaHCO₃ (2×) and saturated NaCl and dried and concentrated toa dark semi-solid. The crude product is purified by flash chromatography(EtOAc/CH₂Cl₂, 0-3%) through a 5 gram silica cartridge topped with 1gram of basic alumina to give 72 mg (55%) of1-ethyl-6-methoxy-2-(4-methylsulfanylphenyl)-1H-indole-3-carbonitrile asan off-white solid.

Example 1AP Preparation ofN-{4-[3-cyano-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-phenyl}methanesulfonamide(Compound 478)

A solution ofN-{4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}methanesulfonamide(90 mg, 0.21 mmol), morpholine (0.06 mL, 0.65 mmol), NaI (32 mg, 0.21mmol) and diisopropyl ethylamine (0.06 mL, 0.32 mmol) in CH₃CN (2 mL) isheated in a sealed tube at 100° C. for 25 h. The reaction mixture iscooled to room temperature, diluted with H₂O and extracted with EtOAc(3×). The combined organic phases are washed with saturated NaCl, driedand concentrated. The crude solid is triturated with EtOAc and filteredto give 41 mg (41%) ofN-{4-[3-cyano-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-phenyl}methanesulfonamideas a tan solid.

The following compounds are made similarly: Compounds 479, 480, 481,482, 496, 497 and 498.

Example 1AQ Preparation of 2-morpholin-4-yl-ethanesulfonicacid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide (Compound653)

Step A: A solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, preparedby example 1Ga step B, (0.82 mg, 2.82 mmol), in pyridine (10 mL) istreated dropwise with chloroethyl sulfonylchloride (0.38 mL, 3.66 mmol)at room temperature. After stirring for 4 h, the reaction mixture isquenched with ice-water and enough 6N HCl is added until the pH islowered to 2. The suspension is extracted with hot EtOAc (3×). Theorganic phases are then washed sequentially with 1N HCl, H₂O andsaturated NaCl and dried and concentrated to give ethenesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide as a paleorange solid which is used directly in the next step without furtherpurification.

Step B: A suspension of ethenesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide, preparedabove, (70 mg, 0.18 mmol), morpholine (0.05 mL, 0.55 mmol) in CH₃CN (1.5mL) is heated at reflux for 1.5 h. After cooling to room temperature,the reaction is concentrated and the residue is purified by flashchromatography (acetone/EtOAc, 2/98) over silica gel to afford 89 mg(100%) of 2-morpholin-4-yl-ethanesulfonicacid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide as a tanfoam.

The following compound is made similarly: Compound 654.

Example 1AR Preparation of 2-morpholin-4-yl-ethanesulfonicacid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methyl amide(Compound 668)

A solution of 2-morpholin-4-yl-ethanesulfonicacid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide, preparedin example 1AQ (60 mg, 0.13 mmol) in DMF (3 mL) is treated with K₂CO₃(35 mg, 0.26 mmol) and methyl iodide (0.02 mL, 0.26 mmol). Afterstirring at room temperature for 1.5 h, the reaction mixture is dilutedwith H₂O and extracted with EtOAc (2×). The organic phases are thenwashed with H₂O (3×) and saturated NaCl, and then dried and concentratedto afford a residue. Flash chromatography over silica gel(acetone/EtOAc, 0-2%) gives 31 mg (50%) of2-morpholin-4-yl-ethanesulfonicacid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methyl amide asan off white solid.

The following compounds are made similarly: Compounds 684, 685, 686,687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698.

Example 1AS Preparation of2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(Compound 84)

Step A: A solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, preparedby example 1Ga step B, (2.78 g, 9.55 mmol) in pyridine (40 mL) istreated dropwise with 3-chloropropanesulfonyl chloride (1.45 mL, 11.9mmol) and the reaction is stirred for 4 h at room temperature. Thereaction is diluted with water and enough 6N HCl to lower the pH to 2.The reaction mixture is extracted with EtOAc (3×) and the combinedorganic layers are washed sequentially with 1N HCl, water and saturatedNaCl and then dried and concentrated to give 3.9 g (95%), of3-chloropropane-1-sulfonicacid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide as a brownfoam which is used directly in the next step.

Step B: A solution of 3-chloropropane-1-sulfonicacid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide, preparedabove (3.65 g, 2.33 mmol) in DMF (100 mL) is treated with K₂CO₃ andheated at 70° C. for 2 h. After cooling to room temperature, thereaction mixture is diluted with H₂O and extracted 3× with hot EtOAc.The hot organic layers are washed with warm H₂O (3×) and saturated NaCland dried and concentrated to a solid. Trituration (CH₂Cl₂/hexanes)gives 2.27 g (68%) of2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrileas a light brown solid.

The following compounds are made in similar fashion: Compound 649, 775,809, 969, 980.

Example 1AT Preparation of2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(Compound 666)

Step A: Following the procedure in example 1B step A,2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrileis treated with 1M BBr₃ solution in CH₂Cl₂ at −15° C. for 1.5 h and thenpoured into ice-water and filtered and dried to afford2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrilein nearly quantitative yield.

Step B: Following the procedure in example 1B step B,2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile,K₂CO₃, 2-iodopropane and methyl ethyl ketone are heated at reflux togive, after flash chromatography (EtOAc/CH₂Cl₂, 0-2%), 61% of2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-isopropoxy-1H-indole-3-carbonitrileas an off-white solid.

The following compounds are made similarly: Compounds 667, 699.

Example 1AU Preparation of2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indole-3-carbonitrile(Compound 729)

A mixture of2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile,prepared in example 1AT above (70 mg, 0.25 mmol), K₂CO₃ (75 mg, 0.51mmol), sodium iodide (27 mg, 0.18 mmol), 4-(2-chloroethyl)morpholinehydrochloride (42 mg, 0.25 mmol) in methyl ethyl ketone (3 mL) is heatedin a sealed tube at 100° C. After 13 hours, DMF (3 mL) is added and thereaction is heated for an additional 6 h. After this time, an additional42 mg of 4-(2-chloroethyl)morpholine hydrochloride and 135 mg of K₂CO₃is added and the reaction is heated for an additional 6 h to completethe reaction. The reaction mixture is cooled to room temperature,diluted with water, and extracted with EtOAc (3×). The combined organicphases are washed with water (2×) and saturated NaCl and dried andconcentrated. Pure2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indole-3-carbonitrileis obtained by flash chromatography (MeOH/CH₂Cl₂, 0-6%) to give 29 mg(34%) of a tan solid.

The following compounds are made similarly: Compounds 728 and 730.

Example 1AV Preparation of2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile(Compound 779)

Step A: A solution of2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (585 mg,1.92 mmol) in 10 mL of 1,4-dioxane is treated with ethylisocyanatoacetate (0.25 mL, 2.12 mmol), and the resulting solution isheated to reflux overnight. The solution is allowed to cool, and thesolvent is removed by rotary evaporation. The residual material istriturated with ether, and the resulting precipitate is collected byfiltration and dried under vacuum to afford compound 773 (587 mg, 1.35mmol, 70%).

A similar procedure is used to prepare methyl2-{3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}-3-phenyl-propionate(compound 777).

Step B: A solution of ethyl{3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}-acetate(compound 773, 101 mg, 0.232 mmol) in THF (10 mL) is treated with asolution of potassium tert-butoxide in tert-butanol (0.30 mL, 1.0 M,0.30 mmol), and the resulting mixture is allowed to stir overnight. Thereaction mixture is partitioned between water and ethyl acetate (50 mLeach), and the organic phase is washed with saturated brine. The aqueousphases are extracted with more ethyl acetate, and the extracts arecombined, dried over anhydrous magnesium sulfate, filtered andevaporated. The residual material is separated by column chromatography(eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile,compound 779, which is purified further by trituration with ether,collection by filtration and drying under high vacuum (76 mg, 0.196mmol, 84%).

Example 1AW Preparation of2-[4-(2,4-dioxo-imidazolidin-1-yl)phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile(Compound 776)

A solution of2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (319 mg,1.04 mmol) in 1,4-dioxane (3 mL) is treated with chloroacetyl isocyanate(0.10 mL, 1.17 mmol), and the resulting solution is warmed to 60° C.overnight. The solution is cooled, and DBU (0.20 mL, 1.31 mmol) isadded. This mixture is stirred at ambient temperature overnight, andthen is partitioned between water and ethyl acetate (50 mL each). Theorganic layer is washed with saturated brine, and then dried overanhydrous magnesium sulfate, filtered and evaporated. The residualmaterial is triturated with ether, and the resulting solid is collectedby filtration and dried under high vacuum to afford the title product(319 mg, 0.821 mmol, 79%).

Example 1AX Preparation ofN,N-Dimethyl-2-[4-(3,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carboxamide(Compound 780) andN,N-Dimethyl-6-ethoxy-1-ethyl-2-[4-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide(Compound 781)

Step A. A solution ofethyl{3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}acetate(compound 773, 325 mg, 0.748 mmol), prepared in procedure 1AV, step A,in acetone (5 mL) is treated with HCl (3 mL, 6 N), and the resultingsolution is heated to reflux overnight. The reaction mixture is cooled,and the resulting precipitate is collected by filtration, washed withether and dried under high vacuum to afford the product,6-ethoxy-1-ethyl-2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide(264 mg, 0.650 mmol, 87%).

Step B. Sodium hydride dispersion in mineral oil (75 mg) is washed witha small portion of hexane, and the hexane layer is decanted off. Asolution of6-ethoxy-1-ethyl-2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide(190 mg, 0.468 mmol) in dimethylformamide (2 mL) is added, and themixture is stirred for 1 hour. Then, methyl iodide (0.10 mL, 1.61 mmol)is added by syringe. The resulting mixture is allowed to stir at ambienttemperature overnight and then is poured into 50 mL of ethyl acetate.The organic phase is washed with water (3×50 mL) and saturated brine (20mL), then dried over anhydrous magnesium sulfate, filtered andevaporated. The residual material is separated by column chromatography(1/1 ethyl acetate/hexane, eluting on silica gel 60) to afford the titleproducts, compounds 780 and 781.

Example 1AY Preparation ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-(2-hydroxyethyl)-methanesulfonamide(Compound 828)

Step A: Sodium hydride dispersion in mineral oil (108 mg) is washed witha small portion of hexane, and the hexane layer is decanted off. Asolution ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide(compound 129, 500 mg, 1.35 mmol) in DMF (5 mL) is slowly added. Aftergas evolution is complete, 2-bromoethyl acetate (0.30 mL, 2.64 mmol) andsodium iodide (20 mg) are added. The mixture is stirred at ambienttemperature overnight, and then is poured into 50 mL of ethyl acetate.This is washed with water (3×50 mL) and saturated brine (20 mL), thendried over anhydrous magnesium sulfate, filtered and evaporated. Theresidual material is separated by column chromatography (1/1 ethylacetate/hexane, eluting on silica gel 60) to afford compound 815 (364mg, 0.799 mmol, 59%).

Step B: A mixture ofN-(2-acetoxyethyl)-N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide(compound 815, 164 mg, 0.360 mmol) and lithium hydroxide hydrate (45 mg,1.07 mmol) in 5 mL THF/1 mL water is warmed to 60° C. overnight. Themixture is cooled and poured into ethyl acetate (50 mL). This is washedwith water (50 mL) and brine (20 mL), dried over anhydrous magnesiumsulfate, filtered and evaporated to afford a solid. The solid istriturated with ether, collected by filtration and dried under highvacuum to affordN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-(2-hydroxyethyl)methanesulfonamide,compound 828 (137 mg, 0.331 mmol, 92%).

Example 1AZ Preparation of1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-1H-indole-3-carbonitrile(Compound 248)

1-Ethyl-2-(4-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (40 mg,0.14 mmol), prepared as in example 1Ga step B, is combined with K₂CO₃(77 mg, 0.56 mmol), bromoethyl methyl ether (26 μL, 0.28 mmol), and DMF(450 μL). This is stirred at room temperature for 1 hour, and then at75° C. for 3 hours. The reaction mixture is then partitioned between H₂Oand EtOAc. The organic layer is dried and concentrated. Purification bysilica gel chromatography (CH₂Cl₂, 0-5% EtOAc) yields1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-1H-indole-3-carbonitrile(44 mg, 90%) as a white solid.

The following compound is prepared similarly as above: Compound 249.

Example 1BA Preparation of1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile(Compound 261)

Step A:1-Ethyl-6-methoxy-2-[4-(2-hydroxyethoxy)-phenyl]-1H-indole-3-carbonitrile(450 mg, 1.34 mmol), prepared as in example 1AZ, is combined with PPh₃(878 mg, 3.35 mmol) in CH₂Cl₂ (32 mL) at 0° C. N-bromosuccinimide (600mg, 3.37 mmol) is added in one portion. The reaction mixture is stirredat room temperature for 30 minutes. The reaction mixture is washed withaqueous NaHCO₃. The organic layer is dried and concentrated, andpurified by silica gel chromatography (CH₂Cl₂) to yield2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(506 mg, 95%), compound 253 as a white solid.

Step B:2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(40 mg, 0.1 mmol), prepared as in step A above, is combined withmorpholine (50 μL, 0.58 mmol) and acetonitrile (1.0 mL). This is heatedat 85° C. for 2 h. The reaction mixture is then partitioned betweenCH₂Cl₂ and H₂O. The organic layer is dried and concentrated.Purification by silica gel chromatography (6/4, acetone/hexanes) yields1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile(39 mg, 96%) as a white solid.

The following compounds are prepared similarly as above, using differentamines: Compounds 262, 263, 264.

Example 1BB Preparation ofN-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}methanesulfonamide(Compound 268)

Step A:2-[4-(2-Bromoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(258 mg, 0.65 mmol), prepared in example 1BA, step A, is combined withNaN₃ (144 mg, 2.2 mmol), and MeOH (3.2 mL). This is heated overnight at75° C. The reaction mixture is then partitioned between CH₂Cl₂ and H₂O.The organic layer is dried and concentrated. Purification by silica gelchromatography (CH₂Cl₂) yields2-[4-(2-azidoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(187 mg, 80%), compound 266 as a white solid.

Step B:2-[4-(2-Azidoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(410 mg, 1.14 mmol), prepared as in step A, above, is suspended in asolution of MeOH (20 mL) and concentrated HCl (500 μL). Pd/C (150 mg,10%) is added, and this mixture is hydrogenated at 30 p.s.i. for 1 h.This is filtered and the filtrate is concentrated. The filtrate residueis partitioned between EtOAc and 0.5N NaOH. The organic layer is driedand concentrated. Purification by silica gel chromatography (10-30%,MeOH/CH₂Cl₂) yields2-[4-(2-aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(298 mg, 78%), compound 267, as a white solid.

Step C:2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(30 mg, 0.09 mmol), prepared in step B, above, is dissolved in pyridine(300 μL). Methanesulfonyl chloride (8 μL, 0.1 mmol) is added. This isstirred at room temperature for 45 minutes. More methansulfonyl chloride(4 μL, 0.05 mmol) is added. Stirring continues for another hour. Thereaction mixture is partitioned between EtOAc and aqueous HCl. Theorganic layer is dried and concentrated. Purification by silica gelchromatography (1/1 CH₂Cl₂/EtOAc) yieldsN-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl}methanesulfonamide,compound 268 (32 mg, 86%) as a white solid.

The following compound is prepared similarly as above: Compound 269.

Example 1BC Preparation ofN-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}acetamide(Compound 274)

2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(30 mg, 0.09 mmol), prepared as in example 1BB, step B, is dissolved inTHF (400 μL), and Et₃N (24 μL, 0.17 mmol). Acetyl chloride (10 μL, 0.14mmol) is added, and the reaction mixture is stirred at room temperaturefor 2 h. The reaction mixture is partitioned between EtOAc and H₂O. Theorganic layer is dried and concentrated. Purification by silica gelchromatography (EtOAc) yieldsN-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl}acetamide(33 mg, 97%) as a white solid.

Example 1BD Preparation of1-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]ethyl}-3-ethyl-urea(Compound 279)

2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(30 mg, 0.09 mmol), prepared as in example 1BB, is combined with ethylisocyanate (18 μL, 0.21 mmol) and pyridine (300 μL). This mixture isstirred at room temperature for 90 minutes, and is then partitionedbetween EtOAc and aqueous HCl. The organic layer is dried andconcentrated. Purification by silica gel chromatography (EtOAc) yields1-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}-3-ethyl-urea(34 mg, 93%) as a white solid.

Example 1BE Preparation ofN-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]ethyl}formamide(Compound 280)

Acetic anhydride (700 μL) and 98% formic acid (280 μL) are heated at 65°C. for 1 h. This is cooled to 0° C.2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(30 mg, 0.09 mmol), prepared as in example 1BB, is taken up in THF (400μL), and added to the mixed anhydride. This is stirred at 0° C. for 45minutes. The mixture is then portioned between EtOAc and aqueous NaHCO₃.The organic layer is dried and concentrated. Purification by silica gelchromatography (4/1, CH₂Cl₂/acetone) yieldsN-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]-ethyl}formamide(28 mg, 86%) as a white solid.

Example 1BF Preparation of1-ethyl-2-{4-[2-(3-hydroxypyrrolidin-1-yl)-2-oxo-ethoxy]phenyl}-6-methoxy-1H-indole-3-carbonitrile(Compound 285)

Step A: 1-Ethyl-2-(4-hydroxyphenyl)-6-methoxy-1H-indole-3-carbonitrile(559 mg, 1.91 mmol), is used to prepare[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acidtert-butyl ester (780 mg, 100%) utilizing essentially the same procedureas example 1AZ.

Step B: [4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-aceticacid tert-butyl ester (745 mg, 1.83 mmol) is stirred in 20% TFA inCH₂Cl₂ at room temperature for 3 hours. This is concentrated and theresidue is partitioned between H₂O and EtOAc. The organic layer is driedand concentrated. The residue is triturated with CH₂Cl₂ to yield[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid (634mg, 99%) as a white solid.

Step C: [4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-aceticacid (40 mg, 0.12 mmol) is suspended in CH₂Cl₂ (1.65 mmol) and DMF (2μL). Oxalyl chloride (17 μL, 0.19 mmol) is added. This is stirred atroom temperature for 30 minutes. The resulting solution is then pipettedinto a stirring solution of S-3-hydroxypyrrolidine (150 μL) and CH₂Cl₂(3.0 mL). The mixture is washed with aqueous HCl. The organic layer isdried and concentrated. Purification by silica gel chromatography (3/2CH₂Cl₂/acetone) yields1-ethyl-2-{4-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-phenyl}-6-methoxy-1H-indole-3-carbonitrile(40 mg, 79%), compound 285 as a white solid.

Example 1BG Preparation of1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-1H-indole-3-carbonitrile(Compound 332)

Step A:1-Ethyl-2-(4-hydroxy-3-nitrophenyl)-6-methoxy-1H-indole-3-carbonitrile(369 mg, 1.1 mmol), prepared as in example 1Gd, is combined with EtOAc(20 mL) and Pd/C (150 mg, 10%). This mixture is hydrogenated at 30p.s.i. for 1 h. This is filtered through celite. The filtrate isconcentrated and triturated with ether to yield2-(3-amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(307 mg, 91%), compound 322, as a white solid.

Step B:2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(100 mg, 0.33 mmol), prepared as in step A, is combined with CDI (83 mg,0.51 mmol), and THF (1.1 mL). This is heated at 65° C. for 1 hour. Thereaction mixture is partitioned between EtOAc and aqueous HCl. Theorganic layer is dried and concentrated. Purification by silica gelchromatography (9/1, CH₂Cl₂/EtOAc) yields1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-1H-indole-3-carbonitrile(89 mg, 81%) as a white solid.

Example 1BH Preparation of1-ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile(Compound 334)

Step A: Bromoacetic acid (52 mg, 0.37 mmol) is combined with EDCIhydrochloride (62 mg, 0.4 mmol) and acetonitrile (900 μL) to form ahomogeneous solution.2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(100 mg, 0.33 mmol), prepared as in example 1BG, step B, is added to thesolution. A thick paste soon forms. Another 1.1 mL of acetonitrile isadded and the mixture is then stirred at room temperature for 2 hours.The reaction mixture is then partitioned between H₂O and EtOAc. Theorganic layer is dried and concentrated. Purification by silica gelchromatography (4/1, CH₂Cl₂/EtOAc) yields2-chloro-N-[5-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-hydroxyphenyl]acetamide(82 mg, 60%), compound 333, as a white solid.

Step B:2-Chloro-N-[5-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-hydroxy-phenyl]acetamide(57 mg, 0.13 mmol), prepared in step A, is combined with K₂CO₃ (55 mg,0.4 mmol), and DMF (400 μL). This is heated at 80° C. for 1 hour. Thereaction mixture is then partitioned between H₂O and EtOAc. The organiclayer is dried and concentrated. Purification by silica gelchromatography (9/1, CH₂Cl₂/EtOAc) yields1-ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile(45 mg, 90%) as a white solid.

Example 1BI Preparation of1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-1H-indole-3-carbonitrile(Compound 340)

Step A: 4-Aminosalicylic acid (4.0 g, 26 mmol) is suspended in H₂SO₄ (26mL, 2.7M) at −5° C. Sodium nitrite (1.8 g, 26.1 mmol) in H₂O (6.5 mL) iscooled to ice bath temperature and is added dropwise to theaminosalicylic acid mixture over 5 minutes. The resulting suspension isstirred at −5° C. for 15 minutes. A solution of KI (6.8 g, 41 mmol) inH₂SO₄ (13 mL, 1M) is added dropwise to the diazonium salt, withconsiderable evolution of N₂. The reaction mixture is heated at 70° C.for 20 minutes. The reaction mixture is then partitioned between H₂O andEtOAc. The organic layer is dried and concentrated. Purification bysilica gel chromatography (7/3, hexanes/acetone, 1% acetic acid) yields4-iodosalicylic acid (5.33g, 85-90% pure).

Step B: Crude 4-Iodosalicylic acid (1.0 g, 3.8 mmol) is dissolved in THF(28 mL) and Et₃N (1.15 mL, 8.2 mmol). DPPA (1.7 mL, 7.8 mmol) is added.This is heated at 70° C. overnight. The reaction mixture is thenpartitioned between H₂O and EtOAc. The organic layer is dried andconcentrated. Purification by silica gel chromatography (9/1,CH₂Cl₂/EtOAc) yields 472 mg crude intermediate. Trituration with etheryields 6-iodo-3H-benzooxazol-2-one (369 mg, 37%) as a white solid.

Step C: 6-Iodo-3H-benzooxazol-2-one (118 mg, 0.45 mmol) is used toprepare1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-1H-indole-3-carbonitrile,compound 340 (75 mg, 55%), utilizing essentially the same procedure asin example 1Gd.

Example 1BJ Preparation of1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4,-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile(Compound 339)

1-Ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile(20 mg, 0.058 mmol), prepared as in example 1BH, is combined with NaH(14 mg, 60% suspension in oil, 0.35 mmol). THF (300 μL) is added. Thisis stirred at room temperature for 5 minutes. A solution of methyliodide (4.4 μL) in THF (100 μL) is added. This is stirred at roomtemperature for 1 hour. The reaction mixture is partitioned betweenEtOAc and aqueous HCl. The organic layer is dried and concentrated.Purification by silica gel chromatography (9/1, CH₂Cl₂/EtOAc) yields1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4,-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile(16 mg, 76%) as a white solid.

The following compound is prepared similarly: Compound 341.

Example 1BK Preparation of1-ethyl-2-iodo-6-methoxy-5-nitro-1H-indole-3-carbonitrile (Compound 499)

1-Ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.15 mmol),prepared as in example 1Ga, Step A, is suspended in acetic acid (620 μL)at 0° C. Nitric acid (4.25M in AcOH) is added. This is stirred at roomtemperature for 2 hours. The reaction mixture is then partitionedbetween CH₂Cl₂ and H₂O. The organic layer is washed with aqueous NaHCO₃,and then is dried and concentrated. Purification by silica gelchromatography (6/4, CH₂Cl₂/hexanes), followed by ether trituration,yields 1-ethyl-2-iodo-6-methoxy-5-nitro-1H-indole-3-carbonitrile (16 mg,29%) as a yellow solid.

Example 1BL Preparation of1′-ethanesulfonyl-1-ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile(Compound 753)

Step A: 6-Nitroindoline (3.0 g, 18.3 mmol) is dissolved in THF (45 mL)and Et₃N (3.4 mL, 24.4 mmol) at 0° C. Acetyl chloride (1.5 mL, 21 mmol)is added dropwise. The mixture is stirred at room temperature for 30minutes. The mixture is partitioned between EtOAc and aqueous HCl. Theorganic layer is dried and concentrated to yield1-acetyl-6-nitroindoline (3.8 g, 100%) as a yellow solid.

Step B: 1-Acetyl-6-nitroindoline (3.8 g, 18.3 mmol) is suspended inEtOAc (200 mL). Pd/C (650 mg, 10%) is added, and the mixture ishydrogenated at 40-55 p.si.i. for 2 hours. The mixture is then filteredthrough celite. The filtrate is concentrated, and the residue istriturated with ether to yield 1-acetyl-6-aminoindoline (3.18 g, 99%) asan orange solid.

Step C: 1-Acetyl-6-aminoindoline (1.5 g, 8.5 mmol) is used to prepare1-acetyl-6-iodoindoline (1.06 g, 43%), utilizing essentially the sameprocedure in example 1BI, Step A.

Step D: 1-Acetyl-6-iodoindoline (1.06 g, 3.7 mmol), NaOH (1.16 g, 29mmol), EtOH (8 mL), and H₂O (6 mL) are heated at 90° C. overnight. Thereaction mixture is then partitioned between H₂O and EtOAc. The organiclayer is extracted into aqueous HCl. The aqueous layer is in turnbasified with NaOH, and is extracted with EtOAc. The organic layer isdried and concentrated. Hexane trituration yields 6-iodoindoline (577mg, 64%) as a brown solid.

Step E: 1-Iodoindoline (600 mg, 2.45 mmol) is used to prepare1-ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile(535 mg, 67%), utilizing essentially the same procedure as in example1Gd, Step B.

Step F:1-Ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile(30 mg, 0.095 mmol) is used to prepare1′-Ethanesulfonyl-1-Ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile(24 mg, 62%), utilizing the procedure in example 1Y.

The following compounds are prepared similarly as above: Compounds 752and 754.

Example 1BM Preparation of5-acetyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile(Compound 844)

1-Ethyl-6-methoxy-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (100 mg,0.3 mmol), prepared by the method of example 1Gc is suspended in1,2-dichloroethane (500 μL) at 0° C. Acetyl chloride (50 μL, 0.69 mmol)is added, followed by AlCl₃ (55 mg, 0.4 mmol) in one portion. This isstirred at 0° C. for 1 hour, at room temperature for 4 hours, and at 45°C. overnight. The reaction mixture is then partitioned between CH₂Cl₂and H₂O. The organic layer is dried and concentrated. Purification bysilica gel chromatography (195:5 CH₂Cl₂/EtOAc) yields5-acetyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile(33 mg, 29%) as an orange solid.

Example 1BN Preparation of1-ethyl-6-methoxy-5-morpholin-4-ylmethyl-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile(Compound 845)

Step A: 1-Ethyl-6-methoxy-2-(4-nitrophenyl)-1H-indole-3-carbonitrile(100 mg, 0.3 mmol), prepared by the method of example 1Gc, is combinedwith 1,3,5-trioxane (64 mg, 0.71 mmol) and acetic acid (2.0 mL). 33% HBrin acetic acid (2.0 mL) is added. This is stirred at room temperaturefor 4 hours. The reaction mixture is then partitioned between CH₂Cl₂ andH₂O. The organic layer is washed with aqueous NaHCO₃, and issubsequently dried and concentrated. The crude material is carriedthrough to the next step.

Step B: Crude6-bromomethyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile(0.3 mmol) is heated with morpholine (150 μL, 1.75 mmol) and DCE (1.0mL) at 90° C. overnight. The reaction mixture is then partitionedbetween H₂O and EtOAc. The organic layer is dried and concentrated.Purification by silica gel chromatography (50-100%, EtOAc/CH₂Cl₂),followed by trituration with 1/1 hexane/acetone yields1-ethyl-6-methoxy-5-morpholin-4-ylmethyl-2-(4-nitrophenyl)-1H-indole-3-carbonitrile(57 mg, 44% overall yield) as a yellow solid.

Example 1BO2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-1-cyclopropylmethyl-6-methoxy-1H-indole-3-carbonitrile(Compound 716)

Step A: To a solution of 6-methoxyindole (5.88 g, 40.0 mmol) anddi-tert-butyl dicarbonate (9.59 g, 44.0 mmol) in DCM (50 mL) is added,at 40° C. while stirring, DMAP (0.10 g). After stirring overnight, themixture is washed sequentially with 0.1 N HCl, water and brine and driedover anhydrous Na₂SO₄. The solvent is evaporated and the residue ischromatographed (silica gel, EtOAc/hexanes, 1/7) to provide tert-butyl6-methoxy-1H-indole-1-carboxylate (8.48 g, 86%).

Step B: The above Boc-indole (3.08 g, 12.5 mmol) and isopropylborate(4.83 mL, 21.9 mmol) are dissolved in anhydrous THF (20 mL) and thesolution is cooled at 0° C. While stirring, LDA (12.5 mL, 1.5 M mono-THFcomplex in cyclohexane, 18.7 mmol) is added dropwise. The mixture isstirred at 0° C. for 15 min and then room temperature for 0.5 h,followed by the addition of HCl (6 N, 3.0 mL, 18 mmol) in an ice-waterbath. The organic solvent is removed in vacuo and the residue issuspended in H₂O (100 mL) and acidified with HCl (6 N) to pH 4˜5. Theprecipitate is collected via filtration and washed with water andhexanes and dried in air to provide 1-Boc-6-methoxyindole-2-boronic acid(3.38 g, 93%).

Step C: To a solution of 4-iodoanilline (3.18 g, 14.5 mmol) in pyridine(15 mL) at 0° C., is added 3-chloropropanesulfonyl chloride (2.3 mL,18.9 mmol). After the addition, the mixture is stirred for 2 h at roomtemperature, and poured into ice-water (200 mL). The organic isseparated and the aqueous layer is extracted with DCM (2×50 mL). Thecombined organics are washed with HCl (2 N, 2×15 mL), water (2×50 mL)and brine (20 mL) consecutively and dried over anhydrous Na₂SO₄. Thesolvent is then evaporated and the residue is chromatographed to furnish3-chloro-N-(4-iodophenyl)propane-1-sulfonamide (4.68 g, 90%). Thechlorosulfonamide obtained (3.47 g, 9.6 mmol) is then treated with K₂CO₃(3.33 g, 24.1 mmol) in DMF (50 mL) at 50° C. for 2 h. The mixture ispoured into ice-water (300 mL) and the precipitate is collected anddried in air to provide essentially pure2-(4-iodophenyl)isothiazolidine-1,1-dioxide (3.11 g, 100%).

Step D: To a mixture of 1-Boc-6-methoxyindole-2-boronic acid prepared instep B above (0.36 g, 1.25 mmol),2-(4-iodophenyl)isothiazolidine-1,1-dioxide (0.32 g, 1.0 mmol) andPdCl₂(dppf) (0.037 g, 0.05 mmol) in DMF (4.0 mL), is added aqueous K₂CO₃solution (1.5 mL, 2.0 M, 3.0 mmol). The mixture is stirred at roomtemperature overnight and then poured into ice-water (100 mL). Theprecipitate is collected and washed with water and purified by flashcolumn chromatography (silica gel, DCM /EtOAc, 9/1) to furnish1-Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1H-indole(0.43 g, 98%).

The following compound is made similarly: Compound 768

Step D:1-Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1H-indole(1.63 g, 3.7 mmol) is treated with TFA (25 mL) in DCM (25 mL) at roomtemperature for 4 h. After the removal of the volatiles, the residue iscarefully stirred with saturated NaHCO₃ for 0.5 h. The precipitate iscollected via filtration and washed with water thoroughly and dried toprovide essentially pure1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (1.17g, 92%).

Step E: At 0° C.,1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (0.95g, 2.8 mmol) is dissolved in DMF (10 mL) and treated with chlorosulfonylisocyanate (0.36 mL, 4.2 mmol). The mixture is then stirred at roomtemperature overnight and poured into ice-water (150 mL) then stirredfor 0.5 h. The precipitate is collected via filtration and washedthoroughly with water and dried in air to furnish1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole-3-carbonitrile(0.89 g, 87%).

The following compound is prepared in the same fashion as describedabove: Compound 829

Step F: To a solution of1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole-3-carbonitrile(73 mg, 0.2 mmol) and K₂CO₃ (69 mg, 0.5 mmol) in DMF (3.0 mL) is addedcyclopropylmethyl iodide (0.029 mL, 0.3 mmol). The mixture is stirred at50° C. overnight and poured into ice-water (10 mL). The precipitate iscollected via filtration, washed with water and purified by columnchromatography to provide2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1-cyclopropylmethylindole-3-carbonitrile,compound 716 (73 mg, 87%).

The following compounds are prepared in the same fashion as describedabove: Compounds 717, 718, 719, 782, 783, 784.

Example 1BP Preparation of2-[4-(1,1′-dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-3-oxazol-5-yl-1-propyl-1H-indole(Compound 805)

Step A: 2-[4-(1,1′-Dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-indole (900mg, 2.62 mmol), prepared in example 1BO, step D is used to prepare2-[4-(1,1′-dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-1-propyl-1H-indole(608 mg, 60%), utilizing essentially the same procedure as example 1A,Step B.

Step B:2-[4-(1,1′-Dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-1-propyl-1H-indole(50 mg, 0.13 mmol) is used to prepare2-[4-(1,1′-dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-3-oxazol-5-yl-1-propyl-1H-indole(9 mg, 15% overall yield) according to the protocol in example 1P.

Example BQ Preparation of2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile(Compound 842)

Step A: To a solution of 1-ethyl-6-trifluoromethylindole-3-carbonitrile(2.54 g, 10.0 mmol), prepared by the method of procedure 1A, inanhydrous THF (20.0 mL), at −78° C. is added LDA (8.3 mL, 1.5 M mono-THFin cyclohexane, 12.5 mmol) dropwise. The mixture is continued for 0.5 hafter the addition, followed by the addition of hexachloroethane and themixture is then brought to room temperature slowly and stirred for 0.5h. The solvent is then evaporated and the residue is treated with water.The organics are extracted with dichloromethane, washed with water andbrine and dried over anhydrous Na₂SO₄. The crude product obtained afterthe removal of the solvent is chromatographed (silica gel,dichloromethane/hexanes, 3/2) to provide2-chloro-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (1.75 g,64%).

Step B: The chloroindole obtained above (0.27 g, 1.0 mmol), K₂CO₃ (0.35g, 2.5 mmol) and N-Boc-piperazine (0.28 g, 1.5 mmol) are stirred at 70°C. in DMF (5.0 mL) for 3 days and then poured into water (50 mL). Theprecipitate is collected via filtration and washed with water.Chromatography of this crude product (silica gel, dichloromethane/ethylacetate, 9/1) provides4-(3-cyano-1-ethyl-6-trifluoromethyl-1H-indol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester, compound 785 (0.30 g, 71%).

The following compounds are prepared in the same fashion as describedabove, by using other amines: Compounds 514, 785, 786.

Step C:4-(3-cyano-1-ethyl-6-trifluoromethyl-1H-indol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester (0.26 g, 6.1 mmol) is treated with TFA (5 mL) indichloromethane (5 mL) for 1 h at room temperature. After the removal ofthe volatiles, the residue is treated with saturated NaHCO₃ and theprecipitate is collected via filtration, washed with water thoroughlyand dried in air to furnish essentially pure1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile(0.20 g, 100%).

Step D: To a solution of1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile(32 mg, 0.1 mmol), pyridine (0.1 mL) in dichloromethaene (1.0 mL) isadded cyclopropanesulfonyl chloride (28 mg, 0.2 mmol) and the mixture isstirred at room temperature overnight. This is then diluted withdichloromethane (5 mL), washed with HCl (2 N, 2×2 mL), water (2×5 mL)and brine (5 mL) and chromatographed over silica gel(dichloromethane/ethyl acetate, 9/1) to provide2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile,compound 842 (30 mg, 70%).

The following compounds are prepared in the same fashion as describedabove, using corresponding sulfonyl chlorides: Compounds 841, 843.

Example 1BR Ethanesulfonic acid[3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-amide (Compound 835)

Step A: 6-Bromo-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile(0.74 g, 2.0 mmol), compound 831, prepared from 6-bromoindole asdescribed in example 1Gb, is mixed with K₂CO₃ (0.55 g, 4.0 mmol), CuI(0.02 g, 0.1 mmol), tert-butyl carbamate (0.35 g, 3.0 mmol),N,N′-dimethylcyclohexane-1,2-diamine ligand (0.028 g, 0.2 mmol) andanhydrous toluene (5.0 mL) in a sealed tube. The reaction system isflushed with nitrogen and then stirred at 110° C. overnight. Aftercooling, the solvent is replaced with dichloromethane andchromatographed (silica gel, dichloromethane) to provide[3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-carbamic acidtert-butyl ester (0.68 g, 84%), compound 832.

Step B: Compound 832 prepared in step A above (0.63 g, 1.56 mmol) istreated with TFA/DCM (7.5 mL/7.5 mL) at room temperature for 2 h, andthe volatiles are removed in vacuum. The residue is treated withsaturated NaHCO₃ and the precipitate is collected via filtration andwashed thoroughly with water, dried in air to provide6-amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (0.45 g,96%), compound 833.

Step C: The above amine (31 mg, 0.1 mmol) is treated with ethanesulfonylchloride (19 mg, 0.15 mmol) in pyridine (1.0 mL) at room temperatureovernight to provide, after purification using column chromatography,ethanesulfonic acid[3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-amide (83%),compound 835.

The following compounds are prepared in the same fashion as describedabove: Compounds 830, 834, 836 and 837.

Example 1BS Preparation of[3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid ethylester (Compound 838)

6-Amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (31 mg, 0.1mmol), compound 833, prepared in example 1BR, step B is treated withethyl chloroformate (16 mg, 0.15 mmol) in pyridine (1.0 mL) at roomtemperature overnight to furnish, after purification using columnchromatography[3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid ethylester (30 mg, 79%).

Example 1BT Preparation of1-[3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-3-ethyl-urea(Compound 839)

6-Amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (31 mg, 0.1mmol) is treated with ethyl isocyanate (14 mg, 0.2 mmol) indichloromethane (1.0 mL) at 40° C. overnight. The precipitate iscollected via filtration, washed with dichloromethane an dried in air tofurnish,1-[3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-3-ethyl-urea (36mg, 95%).

Example 1BU Preparation of1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea(Compound 442)

To a solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50 mg,0.172 mmol) in THF (2 mL) is added 2-chloroethyl isocyanate (22 uL,0.258 mmol) at room temperature. After stirring overnight at reflux, thereaction mixture is concentrated in vacuo and the residue is dilutedwith ethyl acetate. The resulting semi-solid is triturated with hexaneand the precipitate collected is collected by filtration and washed wellwith 50% ethyl acetate in hexane and dried in vacuo to afford (62 mg,91%) of1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea.

Utilizing essentially the same procedure, the following compounds areprepared: Compounds 295, 362, 395, 396, 397, 398, 399, 400, 401, 402,403, 404, 405, 406, 407, 443, 444, 445, 446, 511, 512, 513, 600, 620,626, 627, 628, 679, 680, 681, 740, 741, 742, 743, 748, 749, 750, 751,774, 817, 818, 846, 847, 848, 954, 955, 956, 957, 958, 987, 999, 1000,1001, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1016, 1017, 1018, 1019,1023, 1024, 1027,1036,1039, 1043, 1045, 1060,1061, 1066, 1067,1070,1080, 1092, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1106,1108, 1118, 1120, 1124, 1125, 1126, 1136, 1137, 1138, 1139, 1143, 1144,1156, 1157, 1162, 1163, 1164, 1165, 1171, 1172, 1173, 1197,1190,1214,1221, 1223, 1224, 1225, 1225, 1227, 1256, 1279, 1301, 1303, 1304,1305,

Example 1BV Preparation of1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile(Compound 771)

To a solution of1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea(100 mg, 0.252 mmol) in MeOH (10 mL) is added aqueous 1M KOH (504 uL)and then stirred at 49° C. for 24 h. The solvents are removed underreduced pressure. The residue is diluted with ethyl acetate and thenwashed with water. The organic layer is dried over anhydrous MgSO₄,filtered and concentrated under reduced pressure. The residue is dilutedwith ethyl acetate and then triturated with hexane and the precipitatecollected by filtration and washed well with 50% ethyl acetate in hexaneand dried in vacuo to afford1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile(56 mg, 62%).

Using essentially the same procedure, the following compounds areprepared: Compounds 770, 778

Example 1BW Preparation of1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-1H-indole-3-carbonitrile(Compound 638)

To a solution of[4-(3-cyano-1-ethyl-6-isopropoxy-1H-indol-2-yl)-phenyl]-carbamic acid2-chloro-ethyl ester (30 mg, 0.07 mmol) in DMF (1 mL) is added aqueousK₂CO₃ (10 mg) and then stirred at 50° C. for 18 h. The reaction mixtureis poured into cold water and the precipitate collected by filtrationand washed with hexane and dried in vacuo to afford the title compound(21 mg, 81%).

The following compounds are made in similar fashion: Compounds 820, 821,863, 864.

Example 1BX Preparation of{3-[3-cyano-1-ethyl-6-(3-pyrrolidin-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamicacid ethyl ester (Compound 530)

Step A: To a solution of[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethylester (1.65 g, 4.37 mmol) in DCM (20 mL) is added 1M BBr₃ in DCM (13.12mL) over a period of 20 min. The reaction mixture is stirred further 1 hat room temperature and then the solvents are removed under reducedpressure. The residue is dissolved in MeOH and then poured into coldwater. The precipitate is collected by filtration and washed with hexaneand dried in vacuo to afford[3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethylester (1.5 g, 98%).

Step B: To a solution of[3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethylester (1.2 g, 2.91 mmol) in DMF (10 mL) is added K₂CO₃ (538 mg, 3.9mmol)and 3-bromo-1-chloropropane (383 uL, 3.9 mmol) and the reaction isstirred for overnight at 50° C. The reaction mixture is then poured intocold water and the precipitate is collected by filtration and washedwith hexane and dried in vacuo to afford 1.1 g, 89% of the desiredproduct.

Step C: To a solution of{3-[3-cyano-1-ethyl-6-(3-pyrrolidin-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamicacid ethyl ester (50 mg, 0.12 mmol) in CH₃CN (2 mL) is added DIPEA (31uL, 0.18 mmol), sodium iodide (20 mg, 0.132 mmol) and pyrrolidine (30uL, 0.36 mmol). The resulting mixture is stirred at reflux temperaturefor overnight. The solvent is evaporated and the residue is diluted withethyl acetate and then triturated with hexane and the precipitatecollected by filtration and washed well with 50% ethyl acetate in hexaneand dried in vacuo to afford1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-1H-indole-3-carbonitrile,compound 638 (46 mg, 85%).

The following compounds are made in similar fashion following steps A-C,above: Compounds 441, 447, 491, 492, 493, 504, 525, 526, 527, 528, 529,531, 532, 533, 534, 535, 536, 537, 538, 539.

Example 1BY Preparation of[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (Compound767)

Step A: The starting material2-(3-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (187 mg,0.642 mmol) is dissolved in anhydrous acetone (3.0 mL). Benzoylisothiocyanate (107 mg, 0.656 mmol) is added to the solution at roomtemperature and the mixture is stirred for 17 h during which time aprecipitate forms. The precipitate is filtered, washed with acetone anddried to give 264 mg of1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea(90% yield) as a light yellow solid.

Step B: A suspension of1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea(241 mg, 0.530 mmol) in methyl alcohol (2.0 ml) and water (0.5 mL) isstirred at room temperature as sodium hydroxide (31 mg, 0.78 mmol) isadded. The reaction mixture is heated to 50° C. for 17 h. The reactionmixture is concentrated to remove methyl alcohol. Water is added to themixture and the solid is filtered, washed with water and dried to give179 mg of [3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea,compound 767 (96% yield) as a white solid.

Example 1BZ Preparation of1-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-1H-indole-3-carbonitrile(Compound 458)

A solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg,0.343 mmol), 4-chloro-2-phenyl-quinazoline (83 mg, 0.34 mmol) anddiisopropylethylamine (0.10 mL, 0.57 mmol) in absolute ethanol (3 mL) isheated to reflux overnight. The solution is cooled and evaporated, andthe residue taken up in ethyl acetate (50 mL). This is washed with waterand saturated brine (50 mL each), then dried over anhydrous sodiumsulfate, filtered and evaporated. The resulting solid is triturated withether, collected by filtration and dried under vacuum to afford1-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-1H-indole-3-carbonitrile(139 mg, 0.280 mmol, 82%).

Example 1CA Preparation of diethyl[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-phosphoramidate(Compound 772)

A solution of2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (148 mg,0.484 mmol), diethyl chlorophosphate (0.086 mL, 0.58 mmol) anddiisopropylethylamine (0.10 mL, 0.57 mmol) in 1,4-dioxane (5 mL) isstirred at ambient temperature for 12 hours, then heated to 80° C. foran additional 24 hours. The solution is cooled and poured into 50 mL ofethyl acetate. This is washed with water and saturated brine (50 mLeach), then dried over anhydrous magnesium sulfate, filtered andevaporated. The residual material is separated by flash chromatography(eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford diethyl[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-phosphoramidate (108mg, 0.245 mmol, 51%) as a white powder after evaporation.

The following examples are made in similar fashion: Compounds 936, 937,942, 943, 944, 1081.

Example 1CB Preparation of1-ethyl-6-methoxy-2-[4-(5-methyl-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-indole-3-carbonitrile(Compound 726)

Step A: To a solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (202 mg,0.693 mmol) in pyridine (2.0 mL) is added theN-β-(chloroethylamino)sulfonyl chloride (222 mg, 1.39 mmol). The mixtureis stirred at room temperature for 17 h then water (12.0 mL) is addedand the mixture is extracted with ethyl acetate (3×2 mL). The extract iswashed with 10% aqueous HCl (2×2 mL), water (2×2 mL), dried over MgSO₄,filtered and concentrated on a rotary evaporator. The crude product ispurified by flash chromatography (0-5%, ethyl acetate/methylenechloride) to give 217 mg ofN-(2-chloro-ethyl)-N′-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenyl]sulfamide,compound 724, as a tan solid (75% yield).

In similar fashion the following compounds are prepared: Compounds 540,541, 542, 574, 576, 704.

Step B: To a solution ofN-(2-chloro-ethyl)-N′-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenyl]sulfamide(100 mg, 0.241 mmol) in anhydrous DMF (1.25 mL), is added potassiumcarbonate (71.0 mg, 0.514 mmol). The mixture is stirred at roomtemperature for 17 h, then diluted with water (7.5 mL). The reactionmixture is extracted with ethyl acetate (3×2 mL) and the extract iswashed with water (2×2 mL), dried over MgSO₄ and concentrated to give2-[4-(1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile,compound 725, as a white solid (84 mg, 88% yield).

In similar fashion the following compound is prepared: Compound 705.

Step C: To a solution of2-[4-(1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(34 mg, 0.086 mmol) in anhydrous DMF (1.0 mL) is added potassiumcarbonate (25 mg, 0.18 mmol) and iodomethane (20.4 mg, 0.144 mmol). Themixture is stirred at room temperature for 2 h and then diluted withwater (6.0 mL) to give a precipitate. The precipitate is filtered,washed with water and dried to give1-ethyl-6-methoxy-2-[4-(5-methyl-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-indole-3-carbonitrile,compound 726, as a white solid (35 mg, 98% yield).

In similar fashion the following compounds are prepared: Compounds 727,1110.

Example 1CC Preparation of[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-fluorophenyl]-carbamicacid propyl ester (Compound 877)

A biphasic mixture of2-(4-amino-3-fluorophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(74 mg, 0.24 mmol), prepared as described in example 1Gb, and propylchloroformate (0.033 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO₃(3 mL) is prepared at 0° C. and then allowed to warm to room temperatureand stirred for 24 h. The reaction is then diluted with H₂O andextracted with EtOAc (2×). The organic phases are washed with H₂O andsaturated NaCl and then dried and concentrated. Flash chromatography(EtOAc/hexanes 10-40%) gives 60 mg (63%) of[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-fluorophenyl]-carbamicacid propyl ester as an off-white solid.

The following compounds are prepared in a similar fashion: Compounds875, 876, 878, 879. By utilizing2-(4-amino-3-methylphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrilethe following compounds are prepared: Compounds: 963, 964, 965.

Utilizing the same starting material and procedures described inexamples 1Y, the following compounds are prepared: Compounds 871, 872,873, 874. In similar fashion, utilizing2-(4-amino-3-methylphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile,the following compounds are prepared: Compounds 959, 960, 961, 962.

Utilizing the same starting material and procedures described inexamples 1BU, the following compounds are prepared: 909, 910, 911. In asimilar fashion, utilizing2-(4-amino-3-methylphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile,the following compounds are prepared: Compound: 966, 967.

Example CD Preparation of cyclopropanecarboxylic acid{4-[3-cyano-1-ethyl-6-(2-imidazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-amide(Compound 1183)

Step A: To a solution of compound2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (3.66 g, 12mmol), prepared as described in example 1Gb, in 20 mL of THF is addedEt₃N (3.37 ml) and cyclopropanecarbonyl chloride (1.6 mL, 18 mmol). Themixture is stirred for 3 h at room temperature. Then water and ethylacetate are added to the reaction mixture. The organic layer isseparated, washed with brine (2×), dried over anhydrous Na₂SO₄, filteredand concentrated. The residue is recrystallized with ethyl acetate andhexane to yield 99% of cyclopropanecarboxylic acid[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide.

Step B: To a solution of cyclopropanecarboxylic acid[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide (4.4 g, 11.8mmol) in 60 mL of DCM is added BBr₃ (6.65 mL, 70 mmol) at −10° C. Afterthe addition, the mixture is stirred for 3 h at 0° C. Then aqueousNaHCO₃ is added to the mixture carefully until it became basic. Thecrude solid is collected by filtration to give 91% ofcyclopropanecarboxylic acid[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-amide and is usedfor the next step without further purification.

Step C: To a solution of cyclopropanecarboxylic acid[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-amide (4 g, 11.6mmol) in 15 mL of MEK is added K₂CO₃ (8 g, 58 mmol) and1-bromo-2-chloro-ethane (6.7 mL, 70 mmol). Then the mixture is heated atreflux overnight. After it is cooled to room temperature, water andethyl acetate are added. The organic layer is separated, washed withbrine (2×), dried over anhydrous Na₂SO₄, filtered and concentrated toyield 81% of the crude cyclopropanecarboxylicacid{4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}-amide.

Step D: To a solution of cyclopropanecarboxylicacid{4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}-amide(102 mg, 0.25 mmol) in 1.5 mL of acetonitrile are added NaI (46 mg,0.275 mmol), K₂CO₃ (138 mg, 1 mmol) and imidazole (51 mg, 0.75 mmol) ina sealed tube. Then the mixture is heated to 90° C. and stirredovernight. After it is cooled to room temperature, water and ethylacetate are added. The organic layer is separated, washed with brine(2×), dried over anhydrous Na₂SO₄, filtered and concentrated. The crudecompound is purified by preparative HPLC to give 71% ofcyclopropanecarboxylicacid{4-[3-cyano-1-ethyl-6-(2-imidazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-amide.

Using the same procedure and substituting the appropriate nucleophilicreagents gives the following compounds: Compounds 952, 1025, 1054, 1090,1091, 1092, 1093, 1184.

Example CE Preparation of ethanesulfonic acid[4-(3-cyano-1-ethyl-6-trifluoromethoxyindol-2-yl)phenyl]amide (Compound881)

Step A: To a suspension of t-BuONO (8.01 mL, 67.5 mmol) and CuCl₂ (7.26g, 54 mmol) in acetonitrile (50 mL), at 61° C. with gentle stirring, isadded 2-nitro-4-trifluoromethoxyaniline (10.0 g, 45.0 mmol) portionwise.The mixture is stirred at this temperature for 2 h after the addition.The solvent is removed on a rotorvap and the residue is treated with HCl(6 N, 200 mL), and extracted with dichloromethane (3×100 mL). Theextracts are combined, dried over anhydrous Na₂SO₄, and passed through ashort silica gel pad. The solvent is removed and the residue is added toa suspension of benzyl cyanoacetate (7.88 g, 45 mmol) and K₂CO₃ (12.42g, 90 mmol) in DMF (100 mL). This mixture is then stirred at 45° C.overnight and poured into ice-water (700 mL), and extracted withdichloromethane (3×100 mL). The organics are dried over anhydrous Na₂SO₄and again passed through a short silica gel pad, eluting with ethylacetate. The solvent is then replaced with EtOH (160 mL), acetic acid(16 mL) and water (16 mL), and the reaction mixture is hydrogenated over5% Pd/C (2.80 g) at 50 psi overnight. The mixture is filtered overCelite and the volatiles are removed in vacuo. The residue is dissolvedin dichloromethane (200 mL), washed with Na₂CO₃ (2 M, 2×50 mL), water(2×50 mL), brine (50 mL) and dried over anhydrous Na₂SO₄. The crudeproduct, obtained after the removal of the solvent, is chromatographed(silica gel, DCM/Hexanes, 1/1) to provide 6-trifluoromethoxyindole (5.70g, 63% based on 2-nitro-4-trifluoromethoxyaniline).

Step B: To a solution of 6-trifluoromethoxyindole (2.68 g, 13.3 mmol) indry DMF (10 mL) at 0° C., is added chlorosulfonylisocyanate (2.35 g,1.44 mL, 16.6 mmol). The mixture is then brought to room temperatureslowly and stirred for 1 h. The mixture is poured into ice (100 mL) andstirred for 1 h. The precipitate is collected by filtration and washedthoroughly with water and dried in vacuo, which is then dissolved in DMF(15 mL). To the solution is added K₂CO₃ and EtI (2.59 g, 1.34 mL, 16.6mmol), and the mixture is stirred at 50° C. overnight. It is then pouredinto ice-water (200 mL). The precipitate is collected by filtration andwashed with water, dried in air and purified by chromatography (silicagel, DCM) to furnish 1-ethyl-6-trifluoromethoxyindole-3-carbonitrile(2.90 g, 86%).

Step C: To a solution of the intermediate (2.03 g, 8.0 mmol) obtainedabove, triisopropylborate (2.16 g, 2.65 mL, 12.0 mmol) in dry THF (15mL) at −78° C. is added LDA (6.7 mL, 1.5 M, 10.0 mmol). The mixture isstirred at −78° C. for 15 min after the addition, then slowly brought toroom temperature and stirred for 30 min. It is then cooled at −78° C.and followed by the addition of 4-iodoaniline (2.10 g, 9.6 mmol),PdCl₂(dppf) (0.29 g, 0.4 mmol), DMF (30 mL) and K₂CO₃ (12.0 mL, 2.0 M,24.0 mmol). The mixture is brought to room temperature slowly andstirred overnight and poured into ice-water (400 mL). The precipitate iscollected and washed with water, chromatographed (silica gel, EtOAc/DCM,0.5/9.5) to furnish2-(4-aminophenyl)-1-ethyl-6-trifluoromethoxyindole-3-carbonitrile (1.99g, 72%).

Step D: To a solution of the compound obtained in step C (31 mg, 0.1mmol) in dry pyridine (1.0 mL) is added ethanesulfonyl chloride (14 μL,0.15 mmol). The mixture is stirred at room temperature overnight anddiluted with water (5 mL). The organic is extracted with DCM (5 mL) andwashed with HCl (2N, 2×3 mL), water (2×4 mL) and brine (3 mL) andchromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the product,ethanesulfonic acid[4-(3-cyano-1-ethyl-6-trifluoromethoxyindol-2-yl)phenyl]amide (33 mg,83%).

Compounds 882, 883, 884, 885, 886, 887, 888, 889 are prepared utilizingthe above route using either the appropriate alkylsulfonyl chlorides(procedure 1Y) or chloroformates (procedure 1AJ).

Example 1CF Preparation of2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-1-ethyl-6-(trifluoromethoxy)indole-3-carbonitrile(Compound 903)

Step A: To a solution of 6-trifluoromethoxyindole (3.01 g, 15.0 mmol)and di-tert-butyl dicarbonate (3.59 g, 16.5 mmol) in DCM (30 mL) at 40°C. is added DMAP (0.04 g) while stirring. After stirring overnight, themixture is washed sequentially with 0.1 N HCl, water and brine and driedover anhydrous Na₂SO₄. The solvent is evaporated and the residue ischromatographed (silica gel, EtOAc/Hexanes, 1/9) to provide tert-butyl6-trifluoromethoxy-1H-indole-1-carboxylate.

Step B: The above Boc-indole and triisopropylborate (4.73 g, 5.8 mL,26.3 mmol) are dissolved in anhydrous THF (20 mL) and the solution iscooled to 0° C. While stirring, LDA (15.0 mL, 1.5 M mono-THF complex incyclohexane, 22.5 mmol) is added dropwise. The mixture is stirred at 0°C. for 15 min and then room temperature for 0.5 h, followed by theaddition of HCl (6 N, 3.75 mL, 22.5 mmol) in an ice-water bath. Theorganic solvent is removed in vacuo and the residue is suspended in H₂O(100 mL) and acidified with HCl (6 N) to pH 4˜5. The precipitate iscollected via filtration and washed with water and hexanes and dried inair to provide 1-Boc-6-trifluoromethoxyindole-2-boronic acid (2.56 g,49%).

Step C: To a mixture of 1-Boc-6-trifluoromethoxyindole-2-boronic acidprepared above (0.74 g, 2.1 mmol),2-(4-iodophenyl)isothiazolidine-1,1-dioxide (0.76 g, 2.4 mmol), andPdCl₂(dppf) (0.08 g, 0.1 mmol) in DMF (6.0 mL), is added K₂CO₃ solution(3.2 mL, 2.0 M, 6.4 mmol). The mixture is stirred at room temperatureovernight and then poured into ice-water (100 mL). The precipitate iscollected and washed with water and purified by flash columnchromatography (silica gel, DCM/EtOAc, 9/1) to furnish1-Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole,which is treated with 50% TFA in DCM (15 mL) at room temperature for 1h. After the removal of the volatiles, the residue is carefully stirredwith saturated NaHCO₃ for 0.5 h. The precipitate is collected viafiltration and washed thoroughly with water and dried to provideessentially pure1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxyindole.

Step D: At 0° C., a solution of the intermediate obtained above in dryDMF (10 mL) is treated with chlorosulfonyl isocyanate (0.38 g, 0.23 mL,2.68 mmol). The mixture is then stirred at room temperature overnightand poured into ice-water (150 mL) then stirred for 0.5 h. Theprecipitate is collected via filtration and washed thoroughly with waterand dried in air to furnish1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxyindole-3-carbonitrile(0.81 g, 90%).

Step E: To a solution of1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxyindole-3-carbonitrile(63 mg, 0.15 mmol) and K₂CO₃ (62 mg, 0.45 mmol) in DMF (2.0 mL) is addedethyl iodide (36 μL, 0.45 mmol). The mixture is stirred at 50° C.overnight and poured into ice-water (10 mL). The precipitate iscollected via filtration, washed with water and purified by columnchromatography to provide2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxy-1-ethylindole-3-carbonitrile(59 mg, 88%).

The following compounds are prepared in the same fashion as describedabove: Compounds 902, 904, 905, 906.

Example 1CG Preparation of[4-(3-cyano-1-cyclopropyl-6-methoxyindol-2-yl)phenyl]carbamic acidisopropyl ester (Compound 1234)

Step A: To a suspension of 2-bromo-4-methoxyphenylacetic acid (24.5 g,100 mmol) in DCM (100 mL), while stirring, is added DMF (˜10 mL) untilall the solid disappears, which is followed by the addition of DCC(22.66 g, 110 mmol) and HOBt (14.85 g, 110 mmol). After stirring at RTfor 10 min, cyclopropylamine (8.55 g, 10.4 mL, 150 mmol) is added to themixture, and the resulting mixture is stirred at room temperature for 4h. The solid is filtered and washed thoroughly with DCM (300 mL). Thefiltrate is cooled to −10° C. and gently stirred for 1 h and filteredagain to remove additional urea by-product. The filtrate is passedthrough a silica gel pad and eluted with DCM/EtOAc, 8/2). After theremoval of the solvent, the cyclopropyl amide intermediate is obtainedas white solid (28.34 g, 100%).

Step B: A mixture of above amide (14.2 g, 50.0 mmol), K₂CO₃ (13.8 g, 100mmol), CuI (0.74 g, 5.0 mmol) and N,N′-dimethylcyclohexanediamine (1.42g, 1.57 mL, 10.0 mmol) in toluene (150 mL) is stirred at 110° C. underN₂ atmosphere for 48 h. After cooling to room temperature, the mixtureis filtered over Celite and washed thoroughly with DCM. The filtrate isevaporated under reduced pressure to dryness and the residue ischromatographed (DCM/EtOAc, 9.5/0.5) to provide the product,1-cyclopropyl-6-methoxyoxindole as pale yellow solid (4.30 g, 42%).

Step C: To a solution of the oxindole obtained above (5.0 g, 24.6 mmol)in dry DCM (25 mL), at 0° C., is added DIBAL-H (1.0 M in DCM, 35.0 mL,35.0 mmol). After the addition, the mixture is stirred at roomtemperature for 4 h and re-cooled to 0° C., followed by the addition ofHCl (2 N) dropwise. The DCM layer is washed with HCl (2 N, 10 mL) waterand brine and dried over anhydrous Na₂SO₄. The crude product obtainedafter the removal of the solvent is chromatographed (hexanes/EtOAc,9.5/0.5) to provide the 1-cyclopropyl-6-methoxyindole as a colorless oil(4.52 g, 98%).

Step D: To a solution of 1-cyclopropyl-6-methoxylindole (3.29 g, 17.6mmol) in dry DMF (30 mL), at 0° C., is added chlorosulfonyl isocyanate(3.11 g, 1.91 mL, 22.0 mmol). After the addition, the mixture is stirredat room temperature for 2 h, followed by aqueous work-up. Chromatography(silica gel, hexanes/EtOAc, 9/1) furnishes3-cyano-1-cyclopropyl-6-methoxyindole (3.05 g, 82%).

Step E: To a solution of the intermediate (2.65 g, 12.5 mmol) obtainedabove and triisopropyl borate (3.38 g, 4.14 mL, 18.8 mmol) in dry THF(18 mL) at −78° C. is added LDA (10 mL, 1.5 M, 15.0 mmol). The mixtureis stirred at −78° C. for 15 min after the addition, then slowly broughtto room temperature and stirred for 30 min. It is then cooled at −78° C.and followed by the addition of 4-iodoaniline (3.29 g, 15.0 mmol),PdCl₂(dppf) (0.46 g, 0.6 mmol), DMF (40 mL) and K₂CO₃ (18.8 mL, 2.0 M,37.6 mmol). The mixture is brought to room temperature slowly andstirred overnight and then poured into ice-water (400 mL). Theprecipitate is collected and washed with water, and after drying, ischromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to furnish2-(4-aminophenyl)-1-cyclopropyl-6-methoxyindole-3-carbonitrile (2.84 g,75%).

Step F: To a solution of the compound obtained in step E (61 mg, 0.2mmol) in dry pyridine (2.0 mL) is added isopropylchloroformate (0.3 mL,1.0 M, 0.3 mmol) in toluene. The mixture is stirred at room temperatureovernight and diluted with water (10 mL). The organic layer is extractedwith DCM (10 mL) and washed with HCl (2N, 2×3 mL), water (2×4 mL) andbrine (3 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) toprovide the product,[4-(3-cyano-1-cyclopropyl-6-methoxyindol-2-yl)phenyl]carbamic acidisopropyl ester (66 mg, 85%).

Compounds 1235 and 1236 are prepared by utilizing the above chemistry.

Example 1CH Preparation of1-allyl-6-methoxy-2-[4-(2-oxopyrrolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile(Compound 938)

Utilizing the procedure described in Example 1Gb, substituting1-allyl-6-methoxy-1H-indole-3-carbonitrile (92.3 mg, 0.43 mmol) and1-(4-iodophenyl)-pyrrolidin-2-one gives 99.0 mg (61.3% yield) ofcompounds 938.

Example 1CI Preparation of6-cyclopropoxy-2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-1-ethyl-1H-indole-3-carbonitrile(Compound 1046)

Step A: Utilizing the procedure described in Example 1B (Step A) gives6-hydroxy-1-ethyl-1H-indole-3-carbonitrile.

Step B: To a solution of 6-hydroxy-1-ethyl-1H-indole-3-carbonitrile(503.9 mg, 2.70 mmol) in 5 mL of DMF is added anhydrous K₂CO₃ (1.12 g,8.12 mmol) and 1-bromo 2-fluoroethane (413.7 mg, 3.29 mmol). Theresulting mixture is stirred at 80° C. until complete consumption of thestarting material as determined by TLC. The reaction mixture is cooled,potassium tert-butoxide (1M solution in THF, 5.5 ml, 5.43 mmol) isadded, and stirring continued at 80° C. overnight. The mixture ispartitioned between EtOAc (30 mL) and 1N HCl (20 mL). The organic phaseis washed with saturated NaHCO₃, saturated NaCl and dried andconcentrated. The product is isolated by chromatography (EtOAc/hexanes,10-25%) over silica gel to afford 430.2 mg (74.9%)1-ethyl-6-vinyloxy-1H-indole-3-carbonitrile as a white solid.

Step C: Via a syringe, diethyl zinc is added to a mixture of1-ethyl-6-vinyloxy-1H-indole-3-carbonitrile (288.1 mg, 1.36 mmol),chloroiodomethane (268.9 mg, 1.53 mmol) and 5 ml of 1,2-dichloroethaneover a period of 10 min, maintaining the temperature at −10° C. Themixture is warmed to 20-25° C. for 20 min., and then cooled back to 0°C. Saturated NH₄Cl (15 mL), concentrated ammonium hydroxide (15 mL), andethyl acetate (15 mL) are added in sequence at this temperature, andstirred for 10 min. After the phases are separated, the aqueous phase isback-extracted with ethyl acetate (10 mL). The combined organic phasesare washed with saturated NH₄Cl (10 mL), dried over MgSO₄ and then thesolution is concentrated and the product is purified by chromatography,eluting with 15-30% ethyl acetate/hexanes to afford 140.5 mg (45.7%yield) of 6-cyclopropoxy-1-ethyl-1H-indole-3-carbonitrile as a yellowsolid.

Step D: Utilizing the same procedure described in Example 1Gbsubstituting 4-iodoaniline with 2-(4-iodo-phenyl)-isothiazolidine1,1-dioxide gives the title compound.

In similar fashion, following steps A to D, above, compound 1047 is alsoprepared.

Example CJ Propane-1-sulfonicacid[4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indoel-2-yl)-phenyl]-amide(Compound 928)

Step A: A solution of 6-difluoromethoxy-1-ethyl-1H-indole-3-carbonitrile(316.3 mg, 1.34 mmol) and triisopropyl borate (402.9 mg, 2.14 mmol) inTHF (15 mL) is cooled to −78° C. and treated with LDA (1.5 M mono-THF incyclohexane, 1.07 mL, 1.61 mmol). After the addition, the acetone/dryice bath is exchanged for an ice water bath and the solution is stirredfurther for 30 min. The solution is cooled to −78° C. and a solution of4-iodoaniline (299.5 mg, 1.37 mmol) in DMF (8 mL), K₂CO₃ (2M, 2.01 mL,6.02 mmol) and PdCl₂dppf (51.3 mg, 0.07 mmol) are added in sequence. Themixture is degassed by three successive cycles of vacuum pumping/N₂purging and is stirred overnight (ca. 16 h.). The reaction mixture ispoured into 4 volumes of water, and 4 volumes of ethyl acetate areadded. The phases are separated, and the aqueous phase is extracted withmore ethyl acetate. The organic phases are washed by water, saturatedNaCl and then dried over anhydrous MgSO₄, filtered and evaporated. Theremaining material is purified by column chromatography, eluting with5-15% ethyl acetate/hexanes on silica gel to yield 304.5 mg (70%) of theaniline intermediate as a white solid.

Step B: Utilizing the same procedure described in Example 1Y andsubstituting n-propylsulfonyl chloride gives the title compound.

The following compounds are made using essentially the same procedureand substituting other sulfonyl chlorides: Compounds 929, 930, 931.

Example 1CK[4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-carbamicacid methyl ester (Compound 1130)

A solution of2-(4-aminophenyl)-6-difluoromethoxy-1-ethyl-1H-indole-3-carbonitrile(200 mg, 0.611 mmol) and methyl chloroformate (95 μL, 1.23 mmol) inethyl acetate (2 mL) is treated with 2 M aqueous potassium carbonatesolution (0.370 mL, 0.74 mmol), and the resulting mixture is stirredvigorously overnight. Saturated brine solution (1 mL) is added, and themixture is stirred for 10 minutes. The organic layer is removed, driedover anhydrous magnesium sulfate, filtered and evaporated. The resultingsolid is triturated with 1/1 ether-hexane, collected by filtration anddried under vacuum to afford the title product as a white solid.

Similarly prepared from appropriate reagents are: Compounds 1131, 1132,1133, 1134, 1135.

Example 1CL1-[4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-3-propyl-urea(Compound 893)

A solution of2-(4-aminophenyl)-6-difluoromethoxy-1-ethyl-1H-indole-3-carbonitrile(200 mg, 0.611 mmol) in 1,2-dichloroethane (2 mL) is treated withn-propylisocyanate (115 mL, 1.23 mmol) and triethylamine (170 mL, 1.22mmol). The resulting solution is stirred at ambient temperature for 12hours, and then concentrated. The residual material is separated bysilica gel chromatography (1/2 ethyl acetate-hexane) to afford the titleproduct as a solid.

Similarly prepared from appropriate reagents are: Compounds 892, 894.

Example 1CM Preparation of morpholine-4-carboxylicacid[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-amide(Compound 1166)

Step A: 6-Ethoxy-1H-indole-3-carbonitrile (2.8 g, 15 mmol), prepared asshown in example 1A, step A, is combined with Cs₂CO₃ (11.6 g, 35.6mmol), DMF (21 mL), and cyclobutyl bromide (1.73 mL, 17.9 mmol) in acapped tube. The reaction mixture is heated at 80° C. for 8 h. This isthen quenched with H₂O (200 mL) and is extracted with EtOAc. The EtOAclayer is backwashed with H₂O, and then with brine. The organic phase isdried and concentrated. Purification by silica gel chromatography(hexanes/CH₂Cl₂, 50-100%) yields1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (3.00 g, 83%) as a whitesolid.

Step B: Following essentially the procedure in example 1Gb,1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (3.0 g, 12.4 mmol) isconverted via Suzuki coupling to yield2-(4-aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (2.60g, 68%) as an off-white solid.

Step C: 2-(4-aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile(40 mg, 0.12 mmol), 4-nitrophenyl chloroformate (60 mg, 0.30 mmol),CH₂Cl₂ (400 μL), and pyridine (25 μL, 0.31 mmol) are stirred at roomtemperature for 1 hour. Morpholine (60 μL, 0.70 mmol) is added. Afterstirring at room temperature for an additional 30 minutes, the reactionmixture is diluted in CH₂Cl₂ and is washed with dilute aqueous NaOH toremove the yellow nitrophenol byproduct. The organic layer is dried andconcentrated. Purification by silica gel chromatography (CH₂Cl₂/EtOAc,7/3) yields morpholine-4-carboxylicacid[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-amide (53mg, 100%) as a white solid.

The following compounds are prepared in a similar fashion, using theappropriate amine in the final step: compounds 1087, 1088, 1089, 1119,1159, 1168, 1191, 1266, 1288, 1324, 1325, 1326.

Example 1CN Preparation ofrac-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamicacid 1-cyclopropyl-ethyl ester (Compound 1147)

2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (50 mg,0.15 mmol), prepared as in example 1CM, step B, is combined with4-nitrophenyl chloroformate (76 mg, 0.38 mmol), DCE (0.5 mL), andpyridine (30 μL, 0.37 mmol). This suspension is stirred at roomtemperature for 1 h. Rac-cyclopropyl methyl carbinol (100 μL, 0.98 mmol)is added. This mixture is heated at 75° C. overnight. The reactionmixture is then diluted in CH₂Cl₂ and is washed with dilute aqueous NaOHto remove the yellow nitrophenol byproduct. The organic layer is driedand concentrated. Purification by silica gel chromatography (CH₂Cl₂)yieldsrac-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamicacid 1-cyclopropyl-ethyl ester (40 mg, 60%) as a white solid.

The following compounds are prepared in a similar fashion, using theappropriate alcohols: Compounds 1146, 1158, 1167, 1192, 1208, 1209,1210, 1215, 1216, 1240, 1241, 1242, 1243, 1244, 1246, 1247, 1248, 1249,1250, 1264, 1265, 1267, 1268, 1281, 1282, 1283, 1286, 1287, 1289, 1290,1291, 1292, 1294, 1295,1296, 1297,1298, 1299, 1312, 1313.

Example 1CO Preparation of1-cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1H-indole-3-carbonitrile(Compound 1239)

Step A: 2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile(600 mg, 1.81 mmol), prepared as in example 1CM, step B, is suspended inCH₂Cl₂ (18 mL), and Et₃N (390 μL, 2.7 mmol). Trifluoroacetic anhydride(310 μL, 2.2 mmol) is added dropwise. The reaction mixture is stirred atroom temperature for 30 minutes, after which time dissolution iscomplete. The reaction mixture is then washed with saturated NaHCO₃solution. The organic layer is dried and concentrated to yieldN-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-2,2,2-trifluoro-acetamide(802 mg, 100%) as a yellow solid.

Step B:N-[4-(3-Cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-2,2,2-trifluoro-acetamide(800 mg, 1.8 mmol) is dissolved in DMF (10 mL). NaH (140 mg, 60% oilsuspension, 3.5 mmol) is added. This is stirred at room temperature fora few minutes, after which ethyl iodide (176 μL, 2.2 mmol) is added.This is stirred at room temperature overnight, and then at 75° C. for 6h. Additional portions of NaH (200mg, 5.0 mmol) and iodoethane (200 μL,2.5 mmol) are necessary to push the reaction further. This is heatedovernight at 75° C. Additional ethyl iodide (200 μL, 2.5 mmol) is added.This is heated for another 2 h. The reaction mixture is then diluted inH₂O and is extracted into EtOAc. The EtOAc layer is dried andconcentrated. Silica gel chromatography (CH₂Cl₂) yields 384 mg of aninseparable mixture of expectedN-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-N-ethyl-2,2,2-trifluoro-acetamideand hydrolyzed1-cyclobutyl-6-ethoxy-2-(4-ethylamino-phenyl)-1H-indole-3-carbonitrile.

Step C: The crude mixture from the previous step is dissolved inmethanol (5 mL). 6N NaOH (1.0 mL, 6 mmol) is added, and the mixture isheated at 80° C. for 1 h. The reaction mixture is then diluted in H₂Oand is extracted into CH₂Cl₂. The organic layer is dried andconcentrated. Purification by silica gel chromatography (CH₂Cl₂) yieldspure1-cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1H-indole-3-carbonitrile(343 mg, 53% over two steps) as a white solid.

1-Cyclobutyl-2-(4-diethylamino-phenyl)-6-ethoxy-1H-indole-3-carbonitrile(compound 1217, 77 mg, 11%) is isolated as a byproduct of the reactiondescribed in example 1CO, step B.

Example 1CP Preparation of[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-ethyl-carbamicacid cyclopentyl ester (Compound 1251)

1-Cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1H-indole-3-carbonitrile(35 mg, 0.10 mmol), prepared as in example 1CO, step C, is dissolved inpyridine (300 μL). Cyclopentyl chloroformate (25 μL, 0.17 mmol) isadded. The reaction mixture is stirred at room temperature for 2.5 h.More chloroformate (10 μL, 0.07 mmol) is added to drive the reaction tocompletion. After an additional 90 min of stirring, the reaction mixtureis partitioned between aqueous HCl and EtOAc. The organic layer is driedand concentrated. Purification by silica gel chromatography yields[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-ethyl-carbamicacid cyclopentyl ester (41 mg, 87%) as a white solid.

Compound 1252 is prepared similarly using the appropriate chloroformate.

Example 1CQ Preparation of{4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamicacid isopropyl ester (Compound 1255)

Step A: To a solution[4-(3-cyano-1-cyclobutyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acidisopropyl ester (950 mg, 2.35 mmol) in DCM (10 mL) is added BBr₃ (556uL, 5.9 mmol) over a period of 20 min. The reaction mixture is stirredfurther for 1 h at room temperature and then water (1 mL) is added. Thesolvents are removed under reduced pressure. The residue is dissolved inMeOH and then poured into cold water. The precipitate is collected byfiltration and washed with hexane and dried in vacuo to afford[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acidisopropyl ester (650 mg, 71%).

Step B: To a solution of[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acidisopropyl ester (340 mg, 0.87 mmol) in DMF (2 mL) is added K₂CO₃ (132mg, 0.96 mmol) and 3-bromo-1-chloropropane (172 uL, 1.75 mmol) and thereaction is stirred for 5 h at 60° C. The reaction mixture is thenpoured into cold water and the precipitate is collected by filtrationand washed with hexane and dried in vacuo to afford 370 mg (92%) of thedesired product.

Step C: To a solution of{4-[6-(3-chloro-propoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamicacid isopropyl ester (37 mg, 0.08 mmol) in CH₃CN (1 mL) is added sodiumiodide (71 mg, 0.48 mmol). The resulting mixture is stirred at refluxtemperature overnight. The solvent is then evaporated and the residue isdiluted with anhydrous DMF (1 mL) and then treated with the sodium saltof 1,2,4-triazole (0.16 mmol) at room temperature overnight. The solventis removed under reduced pressure and the residue is diluted with ethylacetate and then washed with water. The organic layer is concentratedand triturated with hexane and the precipitate is collected byfiltration and washed well with 50% ethyl acetate in hexane and dried invacuo to afford{4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamicacid isopropyl ester, compound 1255 (31 mg, 78%).

The following compounds are made in similar fashion following steps A-C,above: Compounds 1253, 1254, 1260, 1261, 1262.

Example 1CR Preparation of{4-[3-cyano-1-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamicacid isopropyl ester (Compound 1276)

Step A: To a solution of[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acidisopropyl ester (390 mg, 1.0 mmol) in CH₃CN (5 mL) is added K₂CO₃ (414mg, 3.0 mmol) and 3-bromo-1-chloroethane (250 uL, 3.0 mmol) and thereaction is stirred for 18 h at 80° C. The reaction mixture is thenpoured into cold water and the precipitate is collected by filtrationand washed with hexane and dried in vacuo to afford 420 mg, 93% of thedesired product.

Step B: To a solution of{4-[6-(3-chloroethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamicacid isopropyl ester (42 mg, 0.09 mmol) in CH₃CN (1 mL) is added sodiumiodide (56 mg, 0.37 mmol). The resulting mixture is stirred at refluxtemperature overnight. The solvent is evaporated and the residue isdiluted with anhydrous DMF (1 mL) and then treated with the sodium saltof 1,2,4-triazole (0.18 mmol) at room temperature for overnight. Thesolvent is removed under reduced pressure and the residue is dilutedwith ethyl acetate and then washed with water. The organic layer isconcentrated and triturated with hexane. The precipitate is collected byfiltration and washed well with 50% ethyl acetate in hexane and dried invacuo to afford{4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamicacid isopropyl ester, compound 1276 (28 mg, 64%).

The following compounds are made in similar fashion following steps Aand B, above: Compounds 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276,1277, 1278.

Example 1CS Preparation of{4-[3-cyano-1-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamicacid 1-cyclopropyl-ethyl ester (Compound 1329)

Step A: To a solution of2-(4-aminophenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (909mg, 3 mmol) in pyridine (5 mL) is added 4-nitrophenyl chloroformate (6mmol) at room temperature and then stirred for 2 h at room temperature.To the reaction is added cyclopropyl methyl carbinol and then stirredfor 8 h at 80° C. The reaction mixture is diluted with 1N HCl and thenextracted with ethyl acetate. The organic layer is concentrated and theresidue is dissolved in EtOAc and triturated with hexane. Theprecipitate is collected by filtration and washed with hexane and driedin vacuo to afford[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid1-cyclopropyl-ethyl ester (996 mg, 80%).

Step B: To a solution of[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid1-cyclopropyl-ethyl ester (1.5 g, 3.61 mmol) in CH₃CN (8 mL) is addedK₂CO₃ (1.5 g, 10.8 mmol) and 2-bromo-1-chloroethane (895 uL, 10.8 mmol)and the reaction is stirred for 18 h at 80° C. The reaction mixture isthen poured into cold water and the precipitate is collected byfiltration and washed with hexane and dried in vacuo to afford 1.46 g,84% of the desired product.

Step C: To a solution of{4-[6-(2-chloroethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamicacid 1-cyclopropyl-ethyl ester (1.46 g, 3.05 mmol) in CH₃CN (10 mL) isadded sodium iodide (1.84 g, 12.22 mmol). The resulting mixture isstirred at reflux temperature overnight. The solvent is evaporated andthe residue is diluted with anhydrous DMF (20 mL) and then used withoutfurther purification. To 1 mL of the DMF solution containing theiodoethyl intermediate (0.153 mmol) is added the sodium salt of1,2,4-triazole (0.31 mmol) and the reaction is stirred at roomtemperature overnight. The reaction mixture is diluted with 0.5 mL DMFand the desired product is purified by preparative LC to give{4-[3-cyano-1-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamicacid cyclopropyl-ethyl ester, compound 1329 (23 mg, 29%).

The following compounds are made in similar fashion following steps A-C,above: Compounds 1327, 1328.

Example 1CT Preparation of1-{4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea(Compound 1314)

Step A: To a solution of1-[4-(3-cyano-1-cyclobutyl-6-methoxy-1H-indol-2-yl)-phenyl]-3-isopropyl-urea(2.21 g, 5.49 mmol in CH₂Cl₂ (30 mL) is added a 1M solution of BBr₃ inCH₂Cl₂ (16.5 mL, 16.5 mmol) at 0° C. The mixture is allowed to warm toroom temperature and kept for 1 h. The reaction mixture is then pouredonto ice and aqueous 1M NaHCO₃ is added until the pH is 7-8. The productis extracted with 100 mL of ethyl acetate (3×) and the organic phasesare washed with 100 mL of saturated NaCl. The organic phases arecombined and dried over MgSO₄. Solvent is removed to recover 1.95 g(92%) of1-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-3-isopropyl-urea,as a tan solid.

Step B: To a solution of1-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-3-isopropyl-urea(750 mg, 1.93 mmol) in 10 mL of acetonitrile is added anhydrous K₂CO₃(800 mg, 5.79 mmol) and 1-bromo-3-chloropropane (382 μL, 3.86 mmol).After stirring overnight at 80° C., the reaction mixture is cooled andsolvent is removed. The reaction is re-suspended in 100 mL of ethylacetate. The organic phase is washed with 200 mL of H₂O, and the aqueousphase is re-extracted 2× with 100 mL of ethyl acetate. The organicphases are combined, dried over MgSO₄ and the solvent is removed toafford 769 mg (86%) of1-{4-[6-(3-chloropropoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-3-isopropyl-ureaas a tan powder.

Step C: To a solution of1-{4-[6-(3-chloropropoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-3-isopropyl-urea(400 mg, 0.860 mmol) in 8 mL of acetonitrile/DMF, (4/1) is addedanhydrous NaI (258 mg, 1.72 mmol). After stirring overnight at 60° C.,the reaction shows conversion to product by LCMS-UV. The reactionmixture is cooled, the solvent is removed and redissolved in DMF to 14.0mL total volume.

Step D: To 1 mL of the DMF solution above,1-{4-[3-cyano-1-cyclobutyl-6-(3-iodopropoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea(34 mg, 0.062 mmol) is added anhydrous 1,2,4-triazole, sodium salt (10.0mg, 0.110 mmol). After stirring overnight at rt, the reaction mixture isfiltered and purified by preparatory LC/UV purification. The solvent isremoved to obtain 12.3 mg (40%) of1-{4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea(compound 1314), as a white powder.

The following compounds are prepared following the above procedure:Compounds 1306, 1307, 1308, 1309, 1315, 1316, 1317, 1318, 1319, 1320,1321, 1323 and 1324.

Example 1CU Preparation of[4-(3-cyano-1-cyclobutyl-6-pyrimidin-2-yl-1H-indol-2-yl)-phenyl]-carbamicacid 1-cyclopropyl-ethyl ester (Compound 2419)

Step A. Into a solution of[4-(3-Cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid1-cyclopropyl-ethyl ester (1.8 g, 4.3 mmol) in CH₂Cl₂ (20 mL) at 0° C.was added pyridine (2.74 g, 34.6 mmol), followed by the slow addition ofa solution of Tf₂O (3.67 g, 13.0 mmol) in CH₂Cl₂ while maintaining thetemperature below 10° C. Upon completion the reaction mixture was washedwith dilute HCl, water and brine, and then dried over MgSO₄,concentrated and triturated with hexanes to provide the product as asolid (1.8 g, 96%).

Step B. A mixture of trifluoro-methanesulfonic acid3-cyano-1-cyclobutyl-2-[4-(1-cyclopropyl-ethoxycarbonylamino)-phenyl]-1H-indol-6-ylester (1.1 g, 2.0 mmol), bis(pinacolato)diboron (0.56 g, 2.2 mmol),Pd(dppf)Cl₂ (49 mg, 0.06 mmol), dppf (24 mg, 0.06 mmol) and potassiumacetate (0.59 g, 6.0 mmol) in dioxane (12 mL) was stirred at 80° C.overnight. The reaction mixture was diluted with EtOAc, washed with H₂Oand brine, dried over Na₂SO₄, concentrated and purified on silica gel(CH₂Cl₂/EtOAc) to provide the product as a solid (0.96 g, 91%).

Step C. A mixture of{4-[3-cyano-1-cyclobutyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indol-2-yl]-phenyl}-carbamicacid 1-cyclopropyl-ethyl ester (0.2 g, 0.38 mmol), 2-chloropyrimidine(39 mg, 0.34 mg), Pd(PPh₃)₄ (22 mg, 0.095 mmol) and cesium fluoride(0.116 g, 0.76 mmol) in DME (2.0 mL) was stirred at 100° C. for 16 h.The mixture was then diluted with EtOAc (20 mL), washed with water andbrine, dried over Na₂SO₄, concentrated and purified on silica gel(CH₂Cl₂/EtOAc) to provide[4-(3-cyano-1-cyclobutyl-6-pyrimidin-2-yl-1H-indol-2-yl)-phenyl]-carbamicacid 1-cyclopropyl-ethyl ester as a solid (0.15 g, 82%).

Example 1CV Preparation of[4-(3-cyano-1-cyclobutyl-6-pyridin-2-yl-1H-indol-2-yl)-phenyl]-carbamicacid 1-cyclopropyl-ethyl ester (Compound 2417)

To a solution of of trifluoro-methanesulfonic acid3-cyano-1-cyclobutyl-2-[4-(1-cyclopropyl-ethoxycarbonylamino)-phenyl]-1H-indol-6-ylester prepared as in Example 1CU Step A (200 mg, 0.37 mmol) in DMF (2.0mL) was added 2-(tributylstannyl)pyridine (160 mg, 0.44 mmol), Pd(PPh₃)₄(21 mg, 0.018 mmol), CuI (7 mg, 0.037 mmol) and CsF (111 mg, 0.73 mmol).The mixture was stirred at 80° C. for 2 h, treated with ether (20 mL)and potassium fluoride (0.5 g). The mixture was stirred for another hourand filtered. The filtrate was washed with water and brine, dried overNa₂SO₄, concentrated and purified on silica gel (CH₂Cl₂/EtOAc) toprovide [4-(3-cyano-1-cyclobutyl-6-pyridin-2-yl-1H-indol-2-yl)carbamicacid 1-cyclopropyl-ethyl ester as a solid (82 mg, 47%).

Example 1CW Preparation of(R)-{4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}carbamicacid 1-cyclopropyl-ethyl ester (Compound 2210)

Step A: To a suspension of 4-iodophenylisocyanate (0.84 g, 3.5 mmol) inCH₂Cl₂ (6 mL) was added (R)-1-cyclopropylethanol (0.67 mL, 6.9 mmol).The solution was then directly subjected to silica gel chromatography(CH₂Cl₂) to provide (R)-(4-iodo-phenyl)carbamic acid 1-cyclopropyl-ethylester (1.05 g, 93%).

Step B: To a solution of(R)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (0.53 g, 2.5 mmol),triisopropylborate (0.86 mL, 3.75 mmol) in THF (7.5 mL) at −78° C. wasadded LDA (1.5M monoTHF in cyclohexane, 3.83 mL, 5.75 mmol). The mixturewas stirred at −78° C. for 10 minutes and then at room temperature for30 minutes, followed by the addition of (4-iodo-phenyl)-carbamic acid1-cyclopropylethyl ester (0.83 g, 2.5 mmol) and PdCl₂(dppf) (0.055 g,0.075 mmol). The reaction mixture was cooled to −78° C. and flushed withnitrogen before the addition of DMF (15 mL) and aq. K₂CO₃ (2.0M, 3.75mL, 7.5 mmol). The cooling bath was removed and the mixture was stirredovernight, poured into ice water (100 mL) and neutralized with aceticacid. The precipitate was filtered, washed with water, dried in air anddissolved in CH₂Cl₂, purified on silica gel (CH₂Cl₂/EtOAc, 9:1) toprovide(R)-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamicacid 1-cyclopropyl-ethyl ester as a solid (0.58 g, 56%).

Step C: A mixture of(R)-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamicacid 1-cyclopropyl-ethyl ester (0.083 g, 0.2 mmol), Cs₂CO₃ (0.163 g, 0.5mmol), 2-chloropyrimidine (0.046 g, 0.4 mmol) in DMF (2.0 mL) wasstirred at 70° C. for 2 h. After cooling to room temperature, themixture was poured into water (15 mL) and the precipitate was collectedvia filtration and washed with water, purified on silica gel(CH₂Cl₂/EtOAc, 9.5:0.5) to provide(R)-{4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}carbamicacid 1-cyclopropyl-ethyl ester (0.073 g, 74%).

Example 1CX Preparation of(R)-{4-[3-cyano-1-cyclopropyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-carbamicacid 1-cyclopropylethyl ester (Compound 2217)

Step A: A mixture of 3-iodoaniso (2.38 mL, 20.0 mmol), cyclopropylamine(2.10 mL, 30.0 mmol), K₃PO₄ (8.48 g, 40.0 mmol), CuI (0.19 g, 1.0 mmol),ethylene glycol (2.23 mL, 40.0 mmol) and isopropanol (20 mL) was stirredat 80° C. overnight. The reaction mixture was concentrated and suspendedin CH₂Cl₂ (100 mL) and water (100 mL). This mixture was then treatedwith 28% aq. ammonia hydroxide until the solids dissolved. The organiclayer was separated, dried over Na₂SO₄ and purified on silica gel(CH₂Cl₂/hexane, 6:4) to provide cyclopropyl(3-methoxyphenyl)amine ascolorless oil (1.52 g, 47%).

Step B: To a mixture of cyclopropyl(3-methoxyphenyl)amine (1.52 g, 9.3mmol), KOH (1.57 g dissolved in 8 mL H₂O) and EtOAc (15 mL) at 0° C. wasadded dropwise, with vigorous stirring, chloroacetyl chloride (1.12 mL,14.0 mmol). The mixture was stirred for additional 30 minutes, washedwith water (3×350 mL), concentrated and purified on silica gel(CH₂Cl₂/hexane, 1:1) to provide2-chloro-N-cyclopropyl-N-(3-methoxy-phenyl)acetamide as a solid (1.80 g,81%).

Step C: A mixture of2-chloro-N-cyclopropyl-N-(3-methoxy-phenyl)-acetamide (1.25 g, 5.2mmol), Pd(OAc)₂ (0.06 g, 0.26 mmol), Et₃N (0.79 g, 1.10 mL, 7.8 mmol),biphenyl-2-yl-di-tert-butyl-phosphane (0.155 g, 0.52 mmol) in toluene(6.0 mL) was stirred at 80° C. overnight. After cooling to roomtemperature the mixture was purified on silica gel (CH₂Cl₂/EtOAc,9.5:0.5) to provide 1-cyclopropyl-6-methoxy-1,3-dihydro-indol-2-one as asolid (0.89 g, 84%).

Step D: To a solution of 1-cyclopropyl-6-methoxy-1,3-dihydro-indol-2-one(5.0 g, 24.6 mmol) in CH₂Cl₂ (25.0 mL), at 0° C. was added DIBAL-H (1.0M in CH₂Cl₂ 33.3 mL, 33.3 mmol). The mixture was then stirred at roomtemperature for 4 h and treated with HCl (1.0 N). The organic layer wasseparated, washed with water and purified on silica gel (CH₂Cl₂) toprovide the indole intermediate, which was then dissolved in dry DMF(40.0 mL) and cooled at 0° C. The solution was treated withchlorosulfonyl isocyanate (5.09 g, 3.13 mL, 36.0 mmol), and stirred at0° C. for 2 h and poured into ice-water (300 mL). The precipitate wascollected by filtration and washed with water and purified on silica gel(hexane/EtOAc, 9:1) to provide1-cyclopropyl-6-methoxy-1H-indole-3-carbonitrile as a solid (3.60 g,69%).

Step E: A solution of 1-cyclopropyl-6-methoxy-1H-indole-3-carbonitrile(3.60 g, 17.0 mmol) in CH₂Cl₂ (50.0 mL) was cooled to −78° C. andtreated with BBr₃ (21.27 g, 8.03 mL, 84.9 mmol), stirred for 10 min andthen brought to room temperature and stirred for additional 30 minutes.The reaction mixture was poured into ice-water (150 mL), neutralizedwith NaHCO₃ and the precipitate was collected by filtration, washed withwater and purified on silica gel (CH₂Cl₂/EtOAc, 9:1) to provide1-cyclopropyl-6-hydroxy-1H-indole-3-carbonitrile as a solid (3.02 g,90%).

Step F: To a solution of1-cyclopropyl-6-hydroxy-1H-indole-3-carbonitrile (0.59 g, 3.0 mmol) andtriisopropylborate (1.03 mL, 4.5 mmol) in THF (15 mL) at −78° C. wasadded LDA (1.5M mono THF in cyclohexane, 4.60 mL, 6.9 mmol) withstirring. The mixture was stirred at −78° C. for 10 min and at roomtemperature for 30 min followed by the addition of(R)-(4-iodo-phenyl)-carbamic acid 1-cyclopropyl-ethyl ester (1.19 g, 3.6mmol) and PdCl₂ (dppf) (0.11 g, 0.15 mmol). The reaction mixture wascooled to −78° C. and flushed with nitrogen whereupon DMF (30 mL) andaq. K₂CO₃ (2.0M, 4.5 mL, 9.0 mmol) was added. The cooling bath wasremoved and the mixture was stirred overnight, poured into ice water(100 mL) and neutralized with acetic acid. The precipitate was filtered,washed with water, dried in air and purified on silica gel(CH₂Cl₂/EtOAc, 9:1) to give(R)-[4-(3-cyano-1-cyclopropyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamicacid 1-cyclopropyl-ethyl ester as a solid (1.16 g, 97%).

Step G: A mixture of(R)-[4-(3-cyano-1-cyclopropyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamicacid 1-cyclopropyl-ethyl ester (0.060 g, 0.15 mmol), Cs₂CO₃ (0.122 g,0.375 mmol), 2-chloropyrimidine (0.034 g, 0.3 mmol) in DMF (1.5 mL) wasstirred at 70° C. for 2 h. After cooling to room temperature the mixturewas poured into water (15 mL) and the precipitate was collected viafiltration, washed with water, and purified on silica gel (CH₂Cl₂/EtOAc,9.5:0.5) to provide(R)-{4-[3-cyano-1-cyclopropyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}carbamicacid 1-cyclopropyl-ethyl ester as a solid (72 mg, 100%).

Example 1CY Preparation of1-{4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-3-isopropylsulfonylurea(Compound 2263)

Step A: To a solution of tert-butanol (10.5 mL, 110.0 mmol) in CH₂Cl₂(100 mL) at 0° C. was added chlorosulfonyl chloride (9.55 mL, 110.0mmol). The mixture was stirred for 5 min and added to a stirred cold (0°C.) mixture of 4-iodoaniline (21.9 g, 100.0 mmol), Et₃N (15.43 mL, 110.0mmol) in CH₂Cl₂ (100 mL). The reaction mixture was stirred at 0° C. for30 minutes and at room temperature for 4.5 h. The reaction mixture wasconcentrated, treated with water (1000 mL) and stirred overnight. Theprecipitate was filtered, washed thoroughly with water and dried invacuum to provide N-Boc-N′-4′-iodophenyl sulfonylurea (36.11 g, 91%).

Step B: To a solution of PPh₃ (7.32 g, 30.0 mmol) in CH₂Cl₂ (20 mL), at0° C., was added DIAD (5.94 mL, 30.0 mmol), and stirred for 0.5 h, thenadded to a mixture of N-Boc-N′-4′-iodophenyl sulfonylurea (7.96 g, 20.0mmol), and isopropanol (2.29 mL, 30.0 mmol) in DCM (20 mL) at 0° C.while stirring. The resulting mixture was stirred at 0° C. for 1 h andthen room temperature for 4 h, and chromatographed (silica gel, CH₂Cl₂).The crude product obtained was suspended in hexanes, stirred for 20 min,filtered and washed with hexanes and dried in air. This was thensuspended in CH₂Cl₂ (40 mL) and treated with TFA (10 mL) for 4 h at roomtemperature. The mixture was carefully neutralized with NaHCO₃ and theCH₂Cl₂ layer was purified on silica gel (CH₂Cl₂/EtOAc, 9:1) to provideN-isopropyl-N′-4′-iodophenylsulfonylurea as a solid (4.89 g, 72%).

Step C: To a solution of1-cyclopropyl-6-hydroxy-1H-indole-3-carbonitrile (0.42 g, 2.0 mmol),triisopropylborate (0.80 mL, 3.5 mmol) in THF (6 mL), at −78° C., wasadded LDA (1.5M monoTHF in cyclohexane, 3.33 mL, 5.0 mmol) withstirring. The mixture was stirred at −78° C. for 10 min and at roomtemperature for 30 min, followed by the addition ofN-isopropyl-N′-4′-iodophenylsulfonylurea (0.96 g, 2.4 mmol) and PdCl₂(dppf) (0.07 g, 0.1 mmol). The reaction mixture was cooled at −78° C.and flushed with nitrogen before the addition of DMF (12 mL) and aq.K₂CO₃ (2.0M, 3.0 mL, 6.0 mmol). The cooling bath was removed and themixture was stirred overnight, poured into ice water (100 mL) andneutralized with acetic acid. The precipitate was filtered and washedwith water, dried in air and purified on silica gel (CH₂Cl₂/EtOAc, 8:2)to give1-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-3-isopropylsulfonylureaas a solid (0.45 g, 74%).

Step D: A mixture of1-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-3-isopropylsulfonylurea(0.085 g, 0.2 mmol), Cs₂CO₃ (0.163 g, 0.5 mmol), 2-chloropyrimidine(0.034 g, 0.3 mmol) in DMF (2.0 mL) was stirred at 70° C. overnight.After cooling to room temperature the mixture was poured into water (15mL) and the precipitate collected via filtration, washed with water andpurified on silica gel (CH₂Cl₂/EtOAc, 8.5:1.5) to provide1-{4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-3-isopropylsulfonylurea(0.061 g, 61%).

Example 1CZ Preparation of1-cyclopropyl-2-(4-isopropylamino-phenyl)-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile(Compound 2434)

Step A: A mixture of 4-iodoaniline (4.38 g, 20.0 mmol), Cs₂CO₃ (16.3 g,50.0 mmol), isopropyliodide (3.0 mL, 30.0 mmol) in DMF (20 mL) wasstirred in a sealed tube at 70° C. for 24 h. The mixture was cooled toroom temperature and poured into water (200 mL). The organic layer wasseparated and washed with water and brine and purified on silica gel(CH₂Cl₂/hexanes, 1:1) to provide (4-iodophenyl)-isopropylamine (3.26 g,63%).

Step B: To a solution of1-cyclopropyl-6-hydroxy-1H-indole-3-carbonitrile (0.59 g, 3.0 mmol),triisopropylborate (1.03 mL, 4.5 mmol) in THF (15 mL) at −78° C. wasadded LDA (1.5M mono THF in cyclohexane, 4.60 mL, 6.9 mmol) withstirring. The mixture was stirred at −78° C. for 10 min and at roomtemperature for 30 min, followed by the addition of(R)-(4-iodo-phenyl)-carbamic acid 1-cyclopropyl-ethyl ester (1.19 g,3.6mmol) and PdCl₂ (dppf) (0.11 g, 0.15 mmol). The reaction mixture wascooled to −78° C., flushed with nitrogen and DMF (30 mL) and aq. K₂CO₃(2.0M, 4.5 mL, 9.0 mmol) added. The cooling bath was removed and themixture was stirred overnight, poured into ice water (100 mL) andneutralized with acetic acid. The precipitate was filtered, washed withwater and CH₂Cl₂ and dried in air to provide1-cyclopropyl-6-hydroxy-2-(4-isopropylamino-phenyl)-1H-indole-3-carbonitrileas a solid (0.85 g, 86).

Step C: A mixture of(1-cyclopropyl-6-hydroxy-2-(4-isopropylamino-phenyl)-1H-indole-3-carbonitrile(0.099 g, 0.3 mmol), Cs₂CO₃ (0.244 g, 0.75 mmol), 2-chloropyrimidine(0.069 g, 0.6 mmol) in DMF (2.0 mL) was stirred at 70° C. overnight.After cooling to room temperature the mixture was poured into water (15mL) and the precipitate was collected via filtration and washed withwater and purified on silica gel (CH₂Cl₂/EtOAc, 9:1) to provide1-cyclopropyl-2-(4-isopropylamino-phenyl)-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrileas a solid (0.104 g, 85%).

Example 1DA Preparation of[4-(3-cyano-1-cyclobutyl-6-cyclopropyl-1H-indol-2-yl)-phenyl]-carbamicacid tert-butyl ester (Compound 2513)

Step A: To a solution of 6-bromo-1-cyclobutyl-1H-indole-3-carbonitrile(1.38 g, 5.0 mmol), and triisopropylborate (1.37 mL, 6.0 mmol) in THF(15.0 mL) at −78° C. was added LDA (1.5M mono THF in cyclohexane, 3.83mL, 5.75 mmol) with stirring. The mixture was stirred at −78° C. for 10min and at room temperature for 30 min followed by addition of(4-iodophenyl)-carbamic acid tert-butyl ester (1.75 g, 5.5 mmol) andPdCl₂(dppf) (0.37 g, 0.5 mmol). The reaction mixture was cooled to −78°C., flushed with nitrogen and DMF (30 mL) and aq. K₂CO₃ (2.0M, 7.5 mL,15.0 mmol) added. The mixture was stirred at −78° C. for 20 min, roomtemperature overnight and poured into ice water (200 mL). Theprecipitate was filtered, washed with water and purified on silica gel(hexanes/EtOAc, 9:1 to 8:2) to give[4-(6-bromo-3-cyano-1-cyclobutyl-1H-indol-2-yl)-phenyl]-carbamic acidtert-butyl ester as a solid (1.23 g, 53%).

Step B: A mixture of[4-(6-bromo-3-cyano-1-cyclobutyl-1H-indol-2-yl)-phenyl]-carbamic acidtert-butyl ester (0.17 g, 0.4 mmol), cyclopropylboronic acid (0.047 g,0.55 mmol), (tert-butyl)₃PHBF₄ (0.014 g, 0.048 mmol), KF (0.093 g, 1.6mmol), and Pd₂(dba)₃-CHCl₃, 0.021 g, 0.02 mmol) in THF (2.0 mL) wasstirred at 60° C. overnight. The mixture was concentrated, taken up inCH₂Cl₂ and filtered through Celite. The solid was washed with CH₂Cl₂ andthe filtrate was purified on silica gel (CH₂Cl₂) to provide[4-(3-cyano-1-cyclobutyl-6-cyclopropyl-1H-indol-2-yl)-phenyl]-carbamicacid tert-butyl ester as a solid (0.10 g, 59%).

Example 1DB{2-chloro-4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-carbamicacid isopropyl ester (Compound 2339)

Step A: To a solution of 1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile(3.0 g, 14.1 mmol) and isopropylborate (5 mL, 21.1 mmol) in anhydrousTHF (40 mL) at 0° C. was added LDA (16.2 mL, 2.0 M inheptane/THF/ethylbenzene, 32.4 mmol) dropwise. The mixture was stirredat 0° C. for 15 min and then at room temperature for 1 h. After coolingthe reaction mixture to 0° C. a solution of 2-chloro-4-iodo-phenylamine(3.9 g, 15.5 mmol) in DMF (40 mL) was added followed by addition ofPdCl₂(dppf) (0.3 g, 0.4 mmol) and aq. K₂CO₃ (14 mL, 2.0 M). The mixturewas warmed to room temperature and continued to stir overnight. Thereaction was diluted with water and then extracted with ethyl acetate.The organic layers was dried, concentrated and triturated withchloroform to provide2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile(3.1 g, 64%) as an off-white solid.

Step B:2-(4-Amino-3-chloro-phenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile(0.67 g, 2 mmol), prepared in step ZA, was dissolved in DMF (7 mL),followed by the addition of 2-chloro-pyrimidine (0.34 g, 3 mmol) andcesium carbonate (1.3 g, 4 mmol). The mixture was brought to 70° C. andstirred for 1 h. After cooling, the solid was filtered and washed withEtOAc. The filtrate was washed with water and brine, dried, concentratedand triturated with ether to provide2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile(0.76 g, 91%) as a white solid.

Step C: To2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile(0.26 g, 0.6 mmol) in CH₂Cl₂ (0.5 mL) and pyridine (0.5 mL) was added asolution of isopropyl chloroformate in toluene (1.0M, 0.8 mL) and themixture was stirred at room temperature overnight. The mixture wasdiluted with aq. HCl (1N) and extracted with CH₂Cl₂. The organic layerwas washed with water and brine, dried, concentrated and purified onsilica gel (40% EtOAc/hexane) to provide{2-chloro-4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-carbamicacid isopropyl ester (0.29 g, 93%) as a white solid.

Example 2 Screening of Low Molecular Weight Compounds Using a Cell-BasedHCV IRES Monocistronic Translation Assay

Chemical libraries are screened using a cell-based monocistronic HCVIRES-regulated translation assay designed to closely mimic natural HCVmRNA translation and then compound analogs are made based on hits in thechemical libraries and screened as well. A DNA construct is prepared,termed pHCVIRESmono, in which HCV IRES sequences (HCV 2b, nucleotides18-347) are inserted between a promoter and the firefly luciferase(Fluc) reporter gene. A stably transfected HepG2 (hepatoblastoma) cellline (termed HepG mono-4) or a Huh7 cell line (termed Huhmono 7), or aHelacell line (termed Helamono), are established by transfection withthe pHCVIRESmono DNA by selecting for resistance to hygromycin.

Example 3 Determination of Selectivity for HCV IRES-RegulatedTranslation Using the Cell-Based Cap-Dependent Translation Assays

Since translation assays are used to screen HCV IRES inhibitors, theselected hits may specifically act on HCV IRES-driven translation or maymodulate general protein synthesis in mammalian cells. The compoundsthat act on general translation will most likely have significanttoxicity. To address this possibility, various cell-based cap-dependenttranslation assays are established for the further evaluation of allselected compounds. Plasmid DNAs containing 130 nucleotides of vectorsequence 5′ to Fluc are constructed. This construct is referred toherein as pLuc. A stable cell line is established in cap-dependenttranslation assays using 293T cells (a human embryonic kidney cellline). HepGmono-4 and pLuc are treated with compound for 20 hours andactivity is determined by quantifying the Fluc signal. A five-foldselectivity between the HCV IRES and cap-dependent translation isconsidered to be desirable. For example, using these cell-basedcap-dependent translation assays, Applicants identified compounds thatshowed IC₅₀ values that were at least 5-fold greater in thecap-dependent translation assays than in the HCV IRES translation assay.FIG. 1 shows an example of a hit that was selective against HCVIRES-regulated translation over cap-dependent pLuc translation.Importantly, the compound had the same level of activity in an HCV IRESmonocistronic 293T cell line as in HepGmono-4 (data not shown). It isthus unlikely that the selectivity of the compounds between HepGmono-4(HepG 2) and the cap-dependent translations (293T) is due to thedifferent cell types used.

Additionally, western blotting assays are used to further demonstratethat the compounds selectively inhibit HCV IRES-driven translation. BothHepGmono-4 and pLuc cells are treated with the compounds as describedabove, following treatment with the test compounds for 20 hours, cellsare collected and lysed in Laemmli buffer containing 0.5% SDS. Proteinsare separated on a 10% SDS-PAGE, then transferred onto a nitrocellulosemembrane, and blotted using antibodies against Fluc (RDI) and β-actin(Oncogene). For example, some of the compounds of the present inventionwere tested in this manner and as expected, the compounds thatselectively inhibited HCV IRES-driven translation in assays using Flucsignal as an end point showed comparable reductions of the luciferasereporter protein levels in HepGmono-4 cells and were relatively inactiveagainst pLuc in the Western blot (data not shown). Importantly, thesecompounds did not inhibit the expression of endogenous β-actin, thetranslation of which is cap-dependent in both cell lines. Consistently,compounds that did not show selectivity in the translation assaysinhibited protein accumulation in both the HCV IRES and cap-dependenttranslation assays (data not shown). As expected, the general proteintranslation inhibitor puromycin also inhibited both the HCV IRES-drivenand cap-dependent protein production (data not shown). Therefore, theWestern blot results confirm that the compounds of the present inventionselectively inhibit HCV IRES-driven translation.

Testing conditions for these cell lines are optimized and the effects ofmRNA level on activity of the compounds are controlled by quantitatingFluc mRNA levels by RT real-time PCR. For example, some of the compoundsof the present invention were tested in this manner, and no significantdifferences in Fluc mRNA levels were observed between the HepGmono-4, orthe Helamono cells, or the Huhmono cells, and cap-dependent translationcell lines used (data not shown).

Example 4 Evaluation of the Selectivity for HCV IRES-Driven TranslationUsing Cellular IRES-Mediated Translation Assays

A number of human mRNAs have been shown to harbor IRES elements (18, 19,39, 44, 45, 91, 126, 130). Although the primary sequences and secondarystructures of the HCV IRES are different from those of cellular IRES, animportant test for selectivity is to determine whether the selectedcompounds are active against cellular IRES. The VEGF IRES has poorinitiation activity in in vitro assays, but demonstrates substantialactivity in cell-based translation assays (45). For example, some of thecompounds of the present invention were tested and all of the compoundsthat had good selectivity with respect to cap-dependent translationexhibited at least 5-fold higher IC₅₀ values against the VEGF IRES thanagainst the HCV IRES (data not shown). These data indicate that theselected compounds have selectivity against viral IRES. In addition tohaving different structures, the VEGF IRES also have differentinteractions with non-canonical cellular translation factors. Thesedifferences may contribute to the selectivity of the HCV IRES inhibitorsthat we have identified.

Example 5 Evaluation of Cytotoxicity

Effects on cell proliferation are a critical issue for any drugdiscovery effort. Therefore, a cell proliferation/cytotoxicity assay isused to eliminate any compounds that affect mammalian cell growth. Theeffects of the selected hits on cell proliferation are tested in humancell lines 293 T and Huh7 (a human hepatoblastoma cell line). Cells aregrown in Dulbecco's modified Eagle's medium supplemented with 10% fetalbovine serum, L-glutamine, penicillin, and streptomycin. Cells in logphase are treated with test compounds for three days, with 250 μM beingthe highest concentration of test compound used. The effect of thecompounds on cell proliferation is assessed by using the CellTiter 96AQueous One Solution Cell Proliferation Assay (Promega, Madison, Wis.).Compounds that have at least 5-fold higher CC₅₀ values relative to IC₅₀values in HepGmono-4 are considered to have a sufficient window betweenactivity and cytotoxicity and, hence, are selected for furtherevaluation. For example, some of the compounds of the present inventionwere tested in this manner, and importantly, all compounds that had goodselectivity with respect to cap-dependent translation also demonstrateda greater than 5-fold ratio of CC₅₀ to IC₅₀ values.

Example 6 Evaluation of the Efficacy of the Compounds in the HCVReplicon System

The lack of reliable and readily accessible cell-culture and smallanimal models permissive for HCV replication has limited the developmentof new anti-HCV agents. Self-replicating subgenomic HCV systems, termedHCV replicons, have been described and have been widely used to assessthe efficacy of anti-HCV inhibitors (8, 9, 46, 70, 103, 104). Interferon(IFN) α and inhibitors of the HCV protease and polymerase have beenreported to be active in the HCV replicon system (8, 17, 32, 68, 69,117).

HCV replicons that include bicistronic and monocistronic systems areavailable and can be used for testing the HCV inhibitors. In thebicistronic replicons, the HCV IRES directs the expression of theselective marker (Neo and/or a Fluc reporter), and the EMCV IRESmediates the expression of viral non-structural proteins. In themonocistronic replicon, the HCV IRES directly mediates viral proteinsynthesis. The HCV IRES inhibitors are analyzed in the bicistronicreplicon by quantitating the Fluc reporter signal. Replicon-containingcells are cultured with the compounds of the invention for 2 days or for3 days. Interferon (IFN) α is used as a positive control. For example,the compounds of the present invention were tested in this manner, andthe experiments showed that compounds that selectively inhibited HCVIRES-mediated translation inhibited Fluc expression in the bicistronicreplicon.

In the following table (Table 1),

-   -   -   *=replicon or HCV-PV IC₅₀>2 μM        -   **=replicon or HCV-PV IC₅₀ between 0.5 uM and 2 μM        -   ***=replicon or HCV-PV IC₅₀<0.5 μM

-   Replicon IC₅₀ values are determined by firefly luciferase signal.

HCV-PV IC₅₀ values are determined by viral RNA reduction. TABLE 1 MassReplicon Replicon Compound Melting Spec IC₅₀ μM IC₅₀ μM Number Point (°C.) [M + H] 2-day 3-day ¹H NMR Data 866 143-145 382.5 ** 867 198-200448.26 ** 868 188-190 446.23 *** *** 869 205-206 354.3 ** 870 328.28 **871 158-161 402.24 * 872 176-179 416.28 * 873 183-187 414.27 * 874182-186 448.26 ** 875 136-140 368.15 ** 876 382.18 ** 877 396.19 ** 878396.19 ** 879 400.14 ** 880 310.26 ** 881 194-195 438.2 *** *** 882181-183 452.3 *** 883 198-200 450.2 *** *** 884 195-196 452.3 *** ***885 148-150 466.3 *** 886 173-175 404.2 ** 887 181-183 418.2 ** 888187-189 436.3 ** 889 160-162 432.2 ** 890 158-160 450.3 ** 891 144-146452.3 ** 892 225-226 417.2 ** 893 191-193 431.3 ** 894 180-182 445.3 **895   225-226.7 348.4 ** ¹H NMR (DMSO-d₆, 300 MHz), δ 10.17 (s, 1H),7.73 (d, J = 7.2 Hz, 2H), 7.48-7.43 (m, 3H), 7.17 (s, 1H), 6.61 (d, J =7.5 Hz, 1H), 4.13-4.05 (m, 4H), 2.03 (s, 3H), 1.31 (t, J = 6.6 Hz, 3H),1.12 (t, J = 7.5 Hz, 3H). 896 245.9-247   362.1 ** ¹H NMR (DMSO-d₆, 300MHz), δ 10.13 (s, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.51-7.45 (m, 3H), 7.20(s, 1H), 6.88 (dd, J = 6.9 Hz and 2.1 Hz, 1H), 4.16-4.05 (m, 4H), 2.34(q, J = 7.5 Hz, 2H), 1.33 (t, J = 6.9 Hz, 3H), 1.19-1.04 (m, 6H). 897254.4-256.3 374.1 ** ¹H NMR (DMSO-d₆, 300 MHz), δ 10.45 (s, 1H), 7.78(d, J = 8.7 Hz, 2H), 7.51-7.45 (m, 3H), 7.20 (d, J = 1.8 Hz 1H), 6.88(dd, J = 6.6 Hz and 2.1 Hz, 1H), 4.16-4.05 (m, 4H), 1.81-1.75 (m, 1H),1.34 (t, J = 6.9 Hz, 3H), 1.14 (t, J = 6.9 Hz, 3H), 0.81-0.79 (m, 4H).898 >300° C. 374.5 ** ¹H NMR (DMSO-d₆, 300 MHz), δ decomposed 10.09 (s,1H), 7.80 (d, J = 8.7 Hz, 2H), 7.62-7.45 (m, 3H), 7.20 (d, J = 1.5 Hz,1H), 6.88 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 4.18-4.05 (m, 4H), 2.62-2.56(m, 1H), 1.33 (t, J = 6.9 Hz, 3H), 1.19-1.04 (m, 9H). 899 246.8-249.7386.5 ** ¹H NMR (DMSO-d₆, 300 MHz), δ 9.99 (s, 1H), 7.80 (d, J = 8.4 Hz,2H), 7.51-7.45 (m, 3H), 7.20 (s, 1H), 6.89 (dd, J = 8.7 Hz and 2.4 Hz,1H), 4.16-4.05 (m, 4H), 2.25-2.02 (m, 4H), 2.01-1.86 (m, 1H), 1.84-1.76(m, 1H), 1.34 (t, J = 6.9 Hz, 3H), 1.17 (t, J = 7.8 Hz, 3H). 900   185.7422.4 ** ¹H NMR (DMSO-d₆, 300 MHz), δ 10.44 (s, 1H), 7.79 (d, J = 8.7Hz, 2H), 7.52-7.48 (m, 3H), 7.32-7.19 (m, 6H), 6.88 (dd, J = 8.7 Hz and2.1 Hz, 1H), 4.16-4.05 (m, 4H), 3.66 (s, 2H), 1.35 (t, J = 7.2 Hz, 3H),1.14 (t, J = 7.2 Hz, 3H). 901   160.4 436.5 ** ¹H NMR (DMSO-d₆, 300MHz), δ 10.18 (s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.52-7.45 (m, 3H),7.26-7.13 (m, 6H), 6.89 (dd, J = 8.7 Hz and 1.8 Hz, 1H), 4.16-4.05 (m,4H), 2.92 (t, J = 2.7 Hz, 2H), 2.68-2.62 (m, 2H), 1.33 (t, J = 6.9 Hz,3H), 1.14 (t, J = 6.9 Hz, 3H). 902 233-235 436.1 ** 903 230-232 450.2*** 904 193-195 464.1 ** 905 171-173 468.2 *** *** 906 246-247 480.1 **907 224-225 410.17 ** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J = 8.8Hz), 7.53 (1H, td, J = 7.7, 1.1 Hz), 7.41-7.32 (2H, m), 6.96 (1H, dd, J= 8.5, 2.0 Hz), 6.89 (1H, d, J = 2.0 Hz), 4.16 (2H, q, J = 7.0 Hz), 4.12(2H, q, J = 7.0 Hz), 3.86 (2H, t, J = 6.6 Hz), 3.42 (2H, t, J = 7.4 Hz),2.58 (2H, p, J = 7.0 Hz), 1.48 (3H, t, J = 7.0 Hz), 1.38 (3H, t, J = 7.0Hz). 908 186-189 476.2 ** 909 180-182 381.24 ** 910 195-198 409.26 **911 228-230 395.24 ** 912 217-221 428.2 [MH]⁻ ** 913 200-202 388.2 **914 212-214 402.2 ** 915 200-202 430.2 ** 916 183-185 478.2 ** 917207-209 266.2 ** 918 219-221 277.4 ** 919 181-183 474.2 ** 920 182-183453.3 ** 921 237-238 460.2 ** 922 246-248 474.2 ** 923 225-229 488.2 **924 221-223 486.2 ** 925 190-192 440.2 ** 926 195-196 454.3 ** 927204-206 306.25 ** 928 206-208 432.14 (M − H+) *** *** 929 177-178 432.09*** *** 930 183-184 468.02 *** *** 931 196-197 432.15 (M − H+) *** ***932 184-185 438.22 *** *** 933 156-157 438.21 ** 934 192-193 436.15 ****** 935 152-153 472.14 *** ** 936 191-192 468.23 *** *** ¹H NMR (300MHz, CDCl₃): δ 7.62 (1H, d, J = 9.1 Hz), 7.38 (2H, d, J = 8.3 Hz), 7.23(1H, d, J = 2.3 Hz), 7.12 (2H, d, J = 8.3 Hz), 6.95 (1H, dd, J = 8.8, J= 2.2 Hz), 6.12 (1H, d, J = 9.0 Hz), 4.93 (1H, m), 4.20 (6H, m), 2.85(2H, m), 2.35 (2H, m), 1.96 (2H, m), 1.48 (3H, t, J = 6.9 Hz), 1.37 (6H,t, J = 6.3 Hz) 937 204-205 440.17 *** 938 147-148 372.21 ** 939 253-255332.29 ** 940 58-59 263.20 ** 941 460.19 *** *** 942 209-210 412.18 (M −H+) ** ¹H NMR (300 MHz, DMSO-d₆): δ 8.48 (1H, d, J = 9.0 Hz), 7.48 (1H,d, J = 8.8 Hz), 7.46 (2H, d, J = 8.5 Hz), 7.21 (1H, obscurred), 7.20(2H, d, J = 8.5 Hz), 6.90 (1H, dd, J = 8.8, 2.2 Hz), 4.16 (2H, q, J =7.3 Hz), 4.10 (2H, q, J = 7.0 Hz), 3.69 (6H, d, J = 11.4 Hz), 1.36 (3H,t, J = 7.0 Hz), 1.18 (3H, t, J = 7.0 Hz). 943 219-220 428.25 ** ¹H NMR(300 MHz, DMSO-d₆): δ 8.40 (1H, d, J = 9.0 Hz), 7.49 (1H, d, J = 8.8Hz), 7.45 (2H, d, J = 8.5 Hz), 7.23 (1H, obscurred), 7.21 (2H, d, J =8.5 Hz), 6.91 (1H, dd, J = 8.8, 2.0 Hz), 4.17 (2H, q, J = 7.0 Hz),4.13-3.97 (4H, m), 3.84 (3H, s), 1.24 (6H, td, J = 7.0, 0.6 Hz), 1.15(3H, t, J = 7.0 Hz). 944 223-224 400.20 ** ¹H NMR (300 MHz, DMSO-d₆): δ8.48 (1H, d, J = 9.0 Hz), 7.49 (1H, d, J = 8.8 Hz), 7.46 (2H, d, J = 8.5Hz), 7.22 (1H, d, J = 2.0 Hz), 7.20 (2H, d, J = 8.5 Hz), 6.91 (1H, dd, J= 8.8, 2.0 Hz), 4.17 (2H, q, J = 7.0 Hz), 3.84 (3H, s), 3.68 (6H, d, J =11.1 Hz), 1.19 (3H, t, J = 7.0 Hz). 945 190-193 414.2 ** 946 163-172410.2 *** *** 947 146-148 424.3 *** *** 948 166-167 458.2 *** *** 949decomposed 392.2 ** ¹H NMR (DMSO-d₆, 300 MHz), δ >300 9.94 (s, 1H), 7.66(d, J = 8.7 Hz, 2H), 7.51-7.45 (m, 3H), 7.20 (s, 1H), 6.88 (d, J = 8.7Hz, 1H), 4.16-4.02 (m, 6H), 1.64-1.61 (m, 2H), 1.34 (t, J = 6.9 Hz, 3H),1.15 (t, J = 6.9 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H). 950 decomposed 396.3** ¹H NMR (DMSO-d₆, 300 MHz), δ >300 10.13 (s, 1H), 7.67 (d, J = 8.4 Hz,2H), 7.52-7.46 (m, 3H), 7.20 (s, 1H), 6.89 (d, J = 8.7 Hz, 1H), 4.73(br, 1H), 4.57 (br, 1H), 4.40 (br, 1H), 4.30 (br, 1H), 4.16-4.05 (m,4H), 1.33 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H). 951 decomposed405.1 ** ¹H NMR (CD3Cl, 300 MHz), δ >300 7.62 (d, J = 8.4 Hz, 1H),7.52-7.42 (m, 4H), 6.96 (dd, J = 1.8 Hz and 8.4 Hz, 1H), 6.88 (d, J =1.8 Hz, 1H), 6.71 (s, 1H), 4.86-4.82 (m, 1H), 4.12 (q, J = 6.9 Hz, 4H),3.29 (q, J = 6.3 Hz, 2H), 1.52-1.31 (m, 10H), 0.95 (t, J = 7.5 Hz, 3H).952 not 472.3 ** 1¹H NMR (CD3CN, 300 MHz), δ detected 9.01 (s, 1H), 7.79(d, J = 8.7 Hz, 2H), 7.58-7.49 (m, 3H), 7.11 (d, J = 1.5 Hz, 1H), 6.96(d, J = 8.4 Hz, 1H), 4.31 (t, J = 4.2 Hz, 2H), 4.16 (q, J = 6.9 Hz, 2H),3.34-3.19 (m, 10H), 2.77 (s, 3H), 2.35-2.30 (m, 1H), 1.25 (t, J = 6.9Hz, 3H), 0.92-0.82 (m, 4H). 184-186 442.2 [MH]⁻ ** 954 232-234 395.2 **955 203-206 409.2 ** *** 956 217-220 409.2 *** *** 957 192-195 423.3 ****** 958 210-212 407.2 ** *** 959 169-171 384.19 ** 960 178-180 398.25 **961 174-177 412.24 ** 962 172-174 410.24 ** 963 203-206 364.24 ** 964153-155 378.28 ** 965 156-157 392.27 ** 966 212-215 377.25 ** 967218-221 391.27 ** 968 241-244 412.18 *** ** 969 264-266 434.15 *** ***970 206-208 390.22 *** *** 971 213-215 404.27 *** *** 972 195-196 418.27*** *** 973 190-192 418.27 *** *** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H,d, J = 8.5 Hz), 7.54 (2H, d, J = 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz), 7.21(1H, d, J = 2.2 Hz), 6.95 (1H, dd, J = 8.8, J = 2.2 Hz), 6.70 (1H, s),5.05 (1H, m), 4.94 (1H, m), 4.14 (2H, q, 6.9 Hz), 2.82 (2H, m), 2.33(2H, m), 1.87 (2H, m), 1.51 (3H, t, J = 4.6 Hz), 1.33 (6H, d, J = 6.1Hz). 974 215-217 422.22 *** *** 975 140-141 434.27 ** 976 158-159 428.25** 977 181-182 452.22 *** 978 185-186 482.28 ** 979 179-180 432.26 ****** 980 236-238 436.24 * 981 201-203 416.26 *** *** 982 169-171 422.22 *¹H NMR (300 MHz, DMSO-d₆): δ 10.16 (1H, br), 7.57 (2H, d, J = 8.5 Hz),7.52 (1H, d, J = 8.5 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.33 (1H, d, J = 2.0Hz), 6.93 (1H, dd, J = 8.5, 2.0 Hz), 4.13 (2H, d, J = 7.0 Hz), 3.85 (3H,s), 2.77 (1H, p, J = 6.3 Hz), 0.98 (6H, d, J = 6.3 Hz), 0.96-0.88 (1H,m), 0.34-0.27 (2H, m), 0.05-0.00 (2H, m). 983 217-219 386.22 ** ¹H NMR(300 MHz, DMSO-d₆): δ 10.48 (1H, s), 7.80 (2H, d, J = 8.8 Hz), 7.53 (2H,d, J = 8.8 Hz), 7.52 (1H, d, J = 8.6 Hz), 7.32 (1H, d, J = 2.0 Hz), 6.92(1H, dd, J = 8.6, 2.0 Hz), 4.13 (2H, d, J = 6.8 Hz), 3.84 (3H, s), 1.82(1H, p, J = 6.0 Hz), 0.99-0.90 (1H, m), 0.89-0.75 (4H, m), 0.33-0.27(2H, m), 0.05-0.00 (2H, m). 984 179-180 390-25 ** ¹H NMR (300 MHz,DMSO-d₆): δ 9.95 (1H, s), 7.67 (2H, d, J = 8.4 Hz), 7.52 (2H, d, J = 8.4Hz), 7.51 (1H, d, J = 8.8 Hz), 7.32 (1H, d, J = 2.3 Hz), 6.91 (1H, dd, J= 8.8, 2.3 Hz), 4.15 (2H, q, J = 7.0 Hz), 4.12 (2H, d, J = 7.0 Hz), 3.84(3H, s), 1.26 (3H, t, J = 7.0 Hz), 1.00-0.90 (1H, m), 0.33-0.25 (2H, m),0.05-0.00 (2H, m). 985 124-125 404.21 ** ¹H NMR (300 MHz, DMSO-d₆): δ9.96 (1H, s), 7.67 (2H, d, J = 8.5 Hz), 7.52 (2H, d, J = 8.5 Hz), 7.50(1H, d, J = 8.8 Hz), 7.32 (1H, d, J = 2.0 Hz), 6.92 (1H, dd, J = 8.8,2.0 Hz), 4.12 (2H, d, J = 6.7 Hz), 4.07 (2H, t, J = 6.8 Hz), 3.84 (3H,s), 1.65 (2H, hx, J = 7.3 Hz), 0.94 (3H, t, J = 7.3 Hz), 0.93-0.89 (1H,m), 0.33-0.26 (2H, m), 0.05-0.00 (2H, m). 986 157-158 404.21 ** ¹H NMR(300 MHz, DMSO-d₆): δ 9.90 (1H, s), 7.67 (2H, d, J = 8.5 Hz), 7.53-7.49(3H, m), 7.32 (1H, d, J = 2.0 Hz), 6.92 (1H, dd, J = 8.8, 2.0 Hz), 4.92(1H, hp, J = 6.3 Hz), 4.12 (2H, d, J = 6.7 Hz), 3.84 (3H, s), 1.27 (6H,d, J = 6.3 Hz), 1.00-0.90 (1H, m), 0.33-0.26 (2H, m), 0.07-0.01 (2H, m).987 183-184 403.26 ** ¹H NMR (300 MHz, DMSO-d6): δ 8.59 (1H, s), 7.56(2H, d, J = 8.5 Hz), 7.47 (1H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.5 Hz),7.29 (1H, d, J = 2.0 Hz), 6.89 (1H, dd, J = 8.8, 2.0 Hz), 6.11 (1H, d, J= 7.6 Hz), 4.10 (2H, d, J = 7.0 Hz), 3.82 (3H, s), 3.75 (1H, m, J = 7.0Hz), 1.08 (6H, d, J = 6.5 Hz), 0.97-0.88 (1H, m), 0.31-0.25 (2H, m),0.04--0.02 (2H, m). 988 168-169 398.25 (M − H+) ** ¹H NMR (300 MHz,DMSO-d₆): δ 10.22 (1H, s), 7.63 (2H, d, J = 8.8 Hz), 7.54 (1H, d, J =8.5 Hz), 7.39 (2H, d, J = 8.8 Hz), 7.35 (1H, d, J = 2.0 Hz), 6.96 (1H,dd, J = 8.8, 2.0 Hz), 5.46 (2H, s), 3.84 (3H, s), 3.22 (2H, q, J = 7.3Hz), 3.17 (3H, s), 1.23 (3H, t, J = 7.3 Hz). 989 195-196 380.18 (M −CH₃O⁻) ** ¹H NMR (300 MHz, DMSO-d₆): δ 7.68 (2H, d, J = 8.8 Hz), 7.54(1H, d, J = 8.5 Hz), 7.38 (2H, d, J = 8.8 Hz), 7.36 (1H, d, J = 2.2 Hz),6.97 (1H, dd, J = 8.5, 2.2 Hz), 5.47 (2H, s), 3.86-3.81 (2H, m), 3.84(3H, s), 3.58 (2H, t, J = 7.3 Hz), 3.17 (3H, s), 2.47-2.41 (2H, m). 990179-180 412.27 (M − H+) ** ¹H NMR (300 MHz, DMSO-d₆): δ 10.22 (1H, s),7.63 (2H, d, J = 8.8 Hz), 7.54 (1H, d, J = 8.5 Hz), 7.38 (2H, d, J = 8.8Hz), 7.34 (1H, d, J = 2.0 Hz), 6.96 (1H, dd, J = 8.5, 2.0 Hz), 5.46 (2H,s), 3.84 (3H, s), 3.20 (2H, t, J = 7.6 Hz), 3.16 (3H, s), 1.72 (2H, hx,J = 7.6 Hz), 0.96 (3H, t, J = 7.5 Hz). 991 179-180 348.17 (M − CH₃O⁻) **¹H NMR (300 MHz, DMSO-d₆): δ 9.97 (1H, s), 7.67 (2H, d, J = 8.8 Hz),7.58 (2H, d, J = 8.8 Hz), 7.53 (1H, d, J = 8.8 Hz), 7.33 (1H, d, J = 2.0Hz), 6.96 (1H, dd, J = 8.8, 2.0 Hz), 5.45 (2H, s), 4.15 (2H, q, J = 7.0Hz), 3.83 (3H, s), 3.16 (3H, s), 1.26 (3H, t, J = 7.0 Hz). 992 155-157362.23 (M − CH₃O⁻) ** ¹H NMR (300 MHz, DMSO-d₆): δ 9.67 (1H, s), 7.68(2H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.53 (1H, d, J = 8.5 Hz),7.34 (1H, d, J = 2.0 Hz), 6.96 (1H, dd, J = 8.5, 2.0 Hz), 5.45 (2H, s),4.07 (2H, t, J = 6.7 Hz), 3.84 (3H, s), 3.31 (3H, s), 1.65 (2H, hx, J =7.0 Hz), 0.94 (3H, t, J = 7.3 Hz). 993 146-148 392.29 (M − H+) ** ¹H NMR(300 MHz, DMSO-d₆): δ 9.90 (1H, s), 7.67 (2H, d, J = 8.6 Hz), 7.57 (2H,d, J = 8.6 Hz), 7.53 (1H, d, J = 8.8 Hz), 7.33 (1H, d, J = 2.0 Hz), 6.96(1H, dd, J = 8.8, 2.0 Hz), 5.45 (2H, s), 4.92 (1H, hp, J = 6.3 Hz), 3.83(3H, s), 3.15 (3H, s), 1.26 (6H, d, J = 6.3 Hz). 994 266-267 375.22 **¹H NMR (300 MHz, DMSO-d₆): δ 11.32 (1H, s), 7.83 (2H, d, J = 8.8 Hz),7.62 (2H, d, J = 8.8 Hz), 7.52 (1H, d, J = 8.5 Hz), 7.25 (1H, d, J = 2.0Hz), 6.93 (1H, dd, J = 8.5, 2.0 Hz), 4.52 (2H, s), 4.20 (2H, q, J = 7.0Hz), 3.85 (3H, s), 1.18 (3H, t, J = 7.0 Hz). 995 179-181 384.2 ** ** 996200-201 398.2 *** ** 997 169-171 412.2 ** 998 166-167 410.2 ** 999172-174 377.3 ** 1000 156-158 391.3 ** 1001 120-124 389.3 ** ** 1002166-158 422.15 ** 1003 189-191 436.15 ** 1004 191-193 450.15 ** 1005169-171 436.15 ** 1006 187-188 450.15 *** ** 1007 179-180 464.20 ***1008 114-115 405.3 ** 1009 202-203 363.3 ** 1010 196-197 377.3 ** 1011205-206 377.3 ** 1012 165-166 391.3 ** 1013 192-193 375.3 ** 1014178.1-183.5 453.1 *** *** ¹H NMR (DMSO-d₆, 300 MHz), δ 8.80 (s, 1H),7.58 (d, J = 6.3 Hz, 2H), 7.48-7.42 (m, 3H), 7.29 (t, J = 5.1 Hz, 2H),7.24-7.19 (m, 4H), 6.89 (d, J = 6.6 Hz, 1H), 6.22 (br, 1H), 4.16-4.08(m, 4H), 3.35-3.33 (m, 2H), 2.75 (t, J = 5.1 Hz, 2H), 1.34 (t, J = 5.1Hz, 3H), 1.16 (t, J = 5.7 Hz, 3H). 1015 150.1-155.6 424.0 ** ¹H NMR(CD₃CN, 300 Hz), δ 8.06 (s, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.55-7.50 (m,3H), 7.04 (d, J = 1.8 Hz, 1H), 6.91 (dd, J = 6.6 Hz and 2.1 Hz, 1H),4.73 (t, J = 3.9 Hz, 1H), 4.57 (t, J = 3.9 Hz, 1H), 4.43 (t, J = 3.9 Hz,1H), 4.34 (t, J = 3.9 Hz, 1H), 4.16-4.09 (m, 4H), 1.65-1.61 (m, 2H),1.40 (t, J = 7.2 Hz, 3H), 1.18-1.06 (m, 2H), 0.74 (t, J = 7.2 Hz, 3H).1016 204.2-209.7 405.2 ** ¹H NMR (DMSO-d₆, 300 Hz), δ 8.74 (s, 1H), 7.59(d, J = 8.4 Hz, 2H), 7.49-7.42 (m, 3H), 7.20 (s, 1H), 6.90 (dd, J = 8.4Hz and 2.4 Hz, 1H), 6.22 (t, J = 5.7 Hz, 1H), 4.17-4.09 (m, 4H),3.14-3.10 (m, 2H), 1.52-1.50 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H),1.13-1.03 (m, 5H), 0.68 (t, J = 6.9 Hz, 3H). 1017 181.3-187.8 419.2 ****** ¹H NMR (DMSO-d₆, 300 Hz), δ 8.67 (s, 1H), 7.58 (d, J = 8.7 Hz, 2H),7.49-7.41 (m, 3H), 7.20 (s, 1H), 6.92 (dd, J = 8.7 Hz and 2.4 Hz, 1H),6.16 (d, J = 7.2, 1H), 4.32-4.02 (m, 4H), 3.80-3.70 (m, 1H), 1.50-1.49(m, 2H), 1.35 (t, J = 6.6 Hz, 3H) 1.11-1.00 (m, 8H), 0.68 (t, J = 7.2Hz, 3H). 1018 172.7-177.6 433.2 *** *** ¹H NMR (DMSO-d₆, 300 Hz), δ 8.71(s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.49-7.41 (m, 3H), 7.20 (s, 1H), 6.90(dd, J = 8.7 Hz and 2.4 Hz, 1H), 6.23 (br, 1H), 4.17-4.09 (m, 4H),3.10-3.09 (m, 2H) 1.50-1.30 (m, 9H), 1.05-1.03 (m, 2H), 0.88 (t, J = 6.6Hz, 3H), 0.69 (t, J = 7.2 Hz, 3H). 1019 153.7-160   481.2 *** *** ¹H NMR(DMSO-d₆, 300 Hz), δ 8.80 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.46-7.45(m, 3H), 7.31-7.20 (m, 6H), 6.90 (dd, J = 8.7 Hz and 2.4 Hz, 1H),6.25-6.24 (m, 1H), 4.17-4.09 (m, 4H), 3.37-3.31 (m, 2H), 2.78-2.71 (m,2H), 1.53-1.51 (m, 2H), 1.35 (t, J = 6.9 Hz, 3H), 1.13-1.00 (m, 2H),0.67 (t, J = 7.2 Hz, 3H). 1020   135-141.7 406.0 *** ** ¹H NMR (CD₃CN,300 Hz), δ 7.91 (s, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.55-7.49 (m, 3H),7.36 (d, J = 2.1 Hz, 1H), 6.91 (dd, J = 6.3 Hz and 2.4 Hz, 1H),4.36-4.02 (m, 4H), 1.66-1.56 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.31 (t,J = 7.2 Hz, 3H), 1.22-1.07 (m, 2H), 0.74 (t, J = 7.2 Hz, 3H). 1021112.1-119.5 420.0 *** *** ¹H NMR (CD₃CN, 300 Hz), δ 7.94 (s, 1H), 7.65(d, J = 8.7 Hz, 2H), 7.55-7.49 (m, 3H), 7.37 (d, J = 2.1 Hz, 1H), 6.91(dd, J = 6.6 Hz and 2.1 Hz, 1H), 4.16-4.07 (m, 4H), 1.72-1.56 (m, 4H),1.40 (t, J = 7.2 Hz, 3H), 1.16-1.06 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H),0.76 (t, J = 7.2 Hz, 3H). 1022 104.3-109.7 420.0 *** * ¹H NMR (DMSO-d₆,300 Hz), δ 9.87 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.51-7.47 (m, 3H),7.21 (s, 1H), 6.90 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 4.96-4.89 (m, 1H),4.16-4.06 (m, 4H), 1.51-1.47 (m, 2H), 1.35 (t, J = 6.9 Hz, 3H),1.21-1.27 (m, 6H), 1.06-0.99 (m, 2H), 0.67 (t, J = 7.2 Hz, 3H). 1023152.7-161.3 433.2 ** ¹H NMR (DMSO-d₆, 300 Hz), δ 8.71 (s, 1H), 7.58 (d,J = 9.0 Hz, 1H), 7.49-7.42 (m, 3H), 7.20 (d, J = 1.8 Hz, 1H), 6.89 (dd,J = 6.6 Hz and 2.1 Hz, 1H), 6.23 (br, 1H), 4.17-4.09 (m, 4H), 3.13-3.06(m, 2H), 1.53-1.28 (m, 9H), 1.05-1.03 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H),0.68 (t, J = 7.2 Hz, 3H). 1024 160.2-167.8 481.2 *** *** ¹H NMR(DMSO-d₆, 300 Hz), δ 8.80 (s, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.49-7.42(m, 3H), 7.33-7.20 (m, 6H), 6.90 (dd, J = 6.9 Hz and 2.1 Hz, 1H), 6.23(br, 1H), 4.17-4.07 (m, 4H), 3.39-3.34 (m, 2H), 2.79-2.71 (m, 2H),1.52-1.49 (m, 2H), 1.36 (t, J = 6.9 Hz, 3H), 1.08-1.01 (m, 2H), 0.68 (t,J = 7.2 Hz, 3H). 1025 133.3-141.8 459.2 ** ¹H NMR (CDCl₃, 300 MHz), δ7.98 (s, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.41(d, J = 7.8 Hz, 2H), 6.91-6.88 (m, 2H), 4.49 (br, 2H), 4.12-4.02 (m,6H), 3.73-3.53 (m, 4H), 3.09 (br, 2H), 1.64 (br, 1H), 1.28-1.26 (m, 3H),1.11 (br, 2H), 0.89-0.87 (m, 2H),. 1026 220-222 432.16 ** *** 1027138-140 443.31 *** *** 1028 *** *** 1029 188 412.8 ** 1030 173 440.2 ***1031 195 426.2 *** 1032 145 424.2 *** 1033 181 444.2 *** 1034 154-155491.3 *** 1035 173-175 497.3 ** 1036 230-235 510.3 ** 1037 155-156430.25 (M − H+) ** 1038 236-238 410.2 ** 1039 243-248 391.3 ** 1040215-217 392.2 ** ** 1041 164-166 412.2 ** *** 1042 135-138 505.4 ** 1043165-166 476.3 ** 1044 167-168 511.3 *** 1045 117 460.3 *** 1046 232-234422.21 *** *** 1047 422.24 *** *** 1048 200-203 440.0 ** 1049 247-249481.3 *** 1050 246-248 381.2 ** 1051 177 423.2 ** 1052 194 424.2 ** 1053236-238 460.2 ** 1054 187.6-195.2 443.2 ** ¹H NMR (CDCl₃, 300 MHz), δ7.91 (br, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.7 Hz, 1H), 7.42(d, J = 8.4 Hz, 2H), 6.95-6.88 (m, 2H), 4.44 (br, 2H), 4.08 (q, J = 6.9Hz, 2H), 3.94-3.90 (m, 2H), 3.62-3.56 (m, 2H), 3.14 (br, 1H), 2.90 (br,2H), 2.17-2.07 (m, 4H), 1.28 (t, J = 7.2 Hz, 3H), 1.15-1.11 (m, 2H),0.87-0.73 (m, 2H). 1055 148.1-153.2 406.0 ** *** ¹H NMR (DMSO-d₆, 300Hz), δ 9.94 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.51-7.47 (m, 3H), 7.23(d, J = 2.4 Hz, 1H), 6.90 (dd, J = 1.8 Hz and 6.6 Hz, 1H), 4.15-4.04 (m,6H), 1.68-1.52 (m, 4H), 1.35 (t, J = 6.9 Hz, 3H), 0.94 (t, J = 7.2 Hz,3H), 0.63 (t, J = 7.2 Hz, 3H). 1056   169-173.9 406.0 *** *** ¹H NMR(DMSO-d₆, 300 Hz), δ 9.87 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.51-7.47(m, 3H), 7.23 (d, J = 1.8 Hz, 1H), 6.90 (dd, J = 2.1 Hz and 6.6 Hz, 1H),4.94-4.90 (m, 1H), 4.15-4.09 (m, 4H), 1.54-1.52 (m, 2H), 1.35 (t, J =6.9 Hz, 3H), 1.28-1.25 (m, 6H), 0.63 (t, J = 7.2 Hz, 3H). 1057184.5-193.9 406.0 ** ¹H NMR (DMSO-d₆, 300 Hz), δ 9.41 (s, 1H), 8.26 (d,J = 6.9 Hz, 2H), 8.01-7.94 (m, 3H), 7.70 (d, J = 2.1 Hz, 1H), 7.41 (dd,J = 2.1 Hz and 6.6 Hz, 1H), 5.21-5.15 (m, 1H), 4.64-4.53 (m, 4H),2.17-2.12 (m, 2H), 2.07 (d, J = 6.9 Hz, 6H), 1.86 (t, J = 6.9 Hz, 3H),1.41 (t, J = 7.5 Hz, 3H). 1058 160.1-166.5 406.0 *** *** ¹H NMR(DMSO-d₆, 300 Hz), δ 9.87 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.51-7.43(m, 3H), 7.20 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 2.1 Hz and 6.6 Hz, 1H),4.94-4.89 (m, 1H), 4.57-4.53 (m, 1H), 4.10 (q, J = 6.9 Hz, 2H), 1.52 (d,J = 6.6 Hz, 6H), 1.35 (t, J = 6.9 Hz, 3H), 1.25 (d, J = 6.6 Hz, 6H).1059   135-142.6 424.0 ** ¹H NMR (CD₃CN, 300 Hz), δ 8.07 (s, 1H), 7.65(d, J = 8.7 Hz, 2H), 7.55-7.49 (m, 2H), 7.04 (d, J = 1.8 Hz, 1H), 6.91(dd, J = 6.6 Hz and 2.1 Hz, 1H), 5.30 (br, 1H), 4.16-4.09 (m, 4H), 4.73(t, J = 4.2 Hz, 1H), 4.57 (t, J = 3.9 Hz, 1H), 4.43 (t, J = 4.2 Hz, 1H),4.34 (t, J = 3.9 Hz, 1H),4.15-4.01 (m, 4H), 1.40 (t, J = 6.9 Hz, 3H),0.87-0.85 (m, 6H). 1060 193.2-199.2 405.1 ** ¹H NMR (CD₃CN, 300 Hz), δ7.65-7.51 (m, 3H), 7.45-7.42 (m, 2H), 7.36-7.31 (m, 1H), 7.04 (d, J =2.1 Hz, 1H),6.94-6.89 (m, 1H), 5.25 (br, 1H), 4.15-4.07 (m, 4H), 3.20(br, 2H), 1.39 (t, J = 6 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H), 0.63 (d, J =6.6 Hz, 6H). 1061 182.7-186.3 419.1 ** ¹H NMR (CD₃CN, 300 Hz), δ7.66-7.53 (m, 3H), 7.45-7.43 (m, 2H), 7.38-7.33 (m, 1H), 7.06-7.05 (m,1H), 6.94-6.91 (m, 1H), 5.34 (br, 1H), 4.15-4.02 (m, 4H), 3.16-3.13 (m,2H), 1.55-1.50 (m, 2H), 1.50-1.39 (m, 3H), 0.98 (t, J = 7.2 Hz, 3H),0.63 (d, J = 6.6 Hz, 6H). 1062 156.7-162.2 378.0 ** ¹H NMR (CDCl₃, 300MHz), δ 7.62 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.46 (d, J =8.7 Hz, 2H), 6.94 (d, J = 8.4 Hz, 1H), 6.85 (m, 2H), 4.11 (q, J = 6.9Hz, 2H), 4.03 (t, J = 7.8 Hz, 2H), 3.82 (s, 3H), 1.72 (q, J = 7.5 Hz,2H), 1.49 (t, J = 6.9 Hz, 3H), 0.78 (t, J = 7.5 Hz, 3H). 1063183.2-187.6 392.1 ** ¹H NMR (CDCl₃, 300 MHz), δ 7.62 (d, J = 8.4 Hz,1H), 7.56 (d, J = 7.8 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 6.94 (d, J =8.4 Hz, 1H), 6.86 (s, 1H), 6.81 (s, 1H), 4.26 (q, J = 6.9 Hz, 2H), 4.11(q, J = 6.9 Hz, 2H), 4.03 (t, J = 7.8 Hz, 2H), 1.72 (q, J = 7.5 Hz, 2H),1.49 (t, J = 6.9 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 0.77 (t, J = 7.5 Hz,3H). 1064 103.2-107.7 410.0 ** ¹H NMR (CDCl₃, 300 MHz), δ 7.62 (d, J =8.7 Hz, 1H), 7.57 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 6.97(s, 1H), 6.95 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H),4.75 (t, J = 4.2 Hz, 1H), 4.59 (t, J = 4.2 Hz, 1H), 4.50 (t, J = 4.5 Hz,1H), 4.41 (t, J = 4.2 Hz, 1H), 4.11 (q, J = 6.9 Hz, 2H), 4.03 (t, J =7.5 Hz, 2H), 1.72 (q, J = 7.5 Hz, 2H), 1.47 (t, J = 6.9 Hz, 3H), 0.78(t, J = 7.2 Hz, 3H). 1065 196.3-220.2 392.0 ** *** ¹H NMR (CDCl₃, 400MHz), δ 7.63 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.42 (d, J =8.4 Hz, 2H), 7.10 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H),4.68-4.61 (m, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 6.8 Hz, 2H),1.58 (d, J = 6.8 Hz, 6H), 1.48 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz,3H). 1066 198.3-205.6 419.0 ** ¹H NMR (CD₃CN, 300 Hz), δ 7.61 (d, J =8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.38(s, 1H) 7.03 (d, J = 1.8 Hz, 1H), 6.91 (dd, J = 6.6 Hz and 2.1 Hz, 1H),5.30 (br, 1H), 4.16-4.09 (m, 4H), 3.18-3.11 (m, 2H), 1.66-1.46 (m, 4H),1.40 (t, J = 6.9 Hz, 3H), 1.16-1.06 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H),0.76 (t, J = 7.5 Hz, 3H). 1067  95-100 504.4 ** 1068 170-174 474.3 **1069 155-156 475.3 ** 1070 208-209 437.22 ** ¹H NMR (300 MHz, DMSO-d₆):δ 8.86 (1H, s), 7.67 (1H, d, J = 2.0 Hz), 7.65 (1H, d, J = 8.5 Hz), 7.61(2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.25 (1H, t, J = 74.4Hz), 7.11 (1H, dd, J = 8.5, 2.0 Hz), 6.40 (1H, t, J = 5.8 Hz), 5.86 (1H,ddt, J = 17.1, 10.4, 5.1 Hz), 5.15 (1H, ddt, J = 17.1, 1.8, 1.7 Hz),5.06 (1H, ddt, J = 10.4, 1.8, 1.7 Hz), 4.12 (2H, d, J = 7.0 Hz), 3.73(2H, narrow m), 0.93-0.84 (1H, m), 0.32-0.23 (2H, m), 0.05-0.00 (2H m).¹⁹F NMR (300 MHz, DMSO-d₆): δ −82.03 (2F, d, J = 73.3 Hz). 1071 125-126452.22 (M − H+) ** * ¹H NMR (300 MHz, CDCl₃): δ 7.69 (1H, d, J = 8.2Hz), 7.56 (2H, d, J = 8.5 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.24 (1H, d, J= 1.8 Hz), 7.07 (1H, dd, J = 8.2, 1.8 Hz), 6.80 (1H, s), 6.52 (1H, t, J= 74.0 Hz), 3.98 (2H, d, J = 7.0 Hz), 3.96 (2H, d, J = 7 Hz), 1.97 (1H,m, J = 6.7 Hz), 1.03-0.94 (1H, m), 0.95 (6H, d, J = 6.7 Hz), 0.46-0.39(2H, m), 0.05-0.00 (2H, m). ¹⁹F NMR (300 MHz, CDCl₃): δ −80.76 (2F, d, J= 73.3 Hz). 1072 197-198 430.30 (M − H+) *** *** 1073 191-192 390.25 **1074 140-141 404.27 ** 1075 140-141 418.27 ** ** 1076 175-176 404.27 ****** 1077 187-188 418.27 *** *** 1078 188-189 430.30 (M − H+) *** ** 1079178-179 452.25 *** *** 1080 221-223 417.28 *** *** ¹H NMR (300 MHz,CDCl₃): 7.61 (1H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.3 Hz), 7.37 (2H, d,J = 8.3 Hz), 7.23 (1H, d, J = 1.0 Hz), 6.96 (1H, dd, J = 8.8, J = 1.7Hz), 4.90 (1H, s), 4.15 (2H, q, J = 6.9), 4.01 (1H, m), 2.82 (2H, m),2.33 (2H, m), 1.81 (2H, m), 1.48 (3H, t, J = 6.9 Hz)), 1.21 (6H, d, J =6.6 Hz). 1081 179-180 452.23 ** (M − H+) 1082 206-207 403.27 ** 1083 156495.3 *** 1084 167 457.2 ** 1085 162 458.4 *** 1086 170 378.2 *** 1087205 405.2 ** 1088 215 403.2 ** 1089 195 389.2 ** 1090 145.6-149.7 475.2** ¹H NMR (CD₃OD, 300 MHz), δ 7.80 (d, J = 8.7 Hz, 2H), 7.58-7.49 (m,3H), 7.22 (d, J = 2.1 Hz, 1H), 7.04 (d, J = 2.1 Hz and 8.7 Hz, 1H), 4.48(t, J = 4.8 Hz, 2H), 4.23 (q, J = 6.9 Hz, 2H), 4.01-3.73 (m, 6H), 3.02(br, 4H), 1.86-1.77 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.00-0.87 (m,4H). 1091 81.4-86.2 461.2 ** ¹H NMR (CD₃OD, 300 MHz), δ 7.78 (d, J = 8.4Hz, 2H), 7.55-7.47 (m, 3H), 7.20 (d, J = 1.8 Hz, 1H), 7.02 (dd, J = 1.8Hz and 8.4 Hz, 1H), 4.46 (t, J = 4.8 Hz, 2H), 4.21 (q, J = 6.6 Hz, 2H),3.81-3.64 (m, 6H), 3.55 (s, 3H), 3.03 (s, 3H), 1.84-1.78 (m, 1H), 1.26(t, J = 7.2 Hz, 3H), 0.99-0.86 (m, 4H). 1092 193.8-197.4 441.2 ** ¹H NMR(CD₃OD, 300 MHz), δ 9.03 (s, 2H), 7.79 (d, J = 8.7 Hz, 2H), 7.56-7.49(m, 3H), 7.14 (d, J = 1.8 Hz, 1H), 6.99 (dd, J = 2.1 Hz and 8.4 Hz, 1H),4.68 (t, J = 4.8 Hz, 2H), 4.44 (t, J = 5.1 Hz, 2H), 4.21 (q, J = 6.9 Hz,2H), 1.85-1.77 (m, 1H), 1.27 (t, J = 6.9 Hz, 3H), 1.01-0.93 (m, 2H),0.91-0.87 (m, 2H). 1093 130.7-134.3 441.2 ** 1094 205.3-208   391.0 **¹H NMR (DMSO-d₆, 300 Hz), δ 8.74 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H),7.49-7.41 (m, 3H), 7.22 (s, 1H), 6.89 (dd, J = 1.8 Hz and 6.9 Hz, 1H),6.22 (t, J = 5.4 Hz, 1H), 4.15-4.06 (m, 4H), 3.14-3.10 (m, 2H),1.58-1.51 (m, 2H), 1.35 (t, J = 6.9 Hz, 3H), 1.05 (t, J = 7.2 Hz, 3H),0.63 (t, J = 7.5 Hz, 3H). 1095 195.3-200.1 405.1 *** *** ¹H NMR(DMSO-d₆, 300 Hz), δ 8.72 (s, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.49-7.41(m, 3H), 7.22 (s, 1H), 6.89 (dd, J = 1.8 Hz and 6.9 Hz, 1H), 6.26 (t, J= 5.4 Hz, 1H), 4.20-4.07 (m, 4H), 3.09-3.03 (m, 2H), 1.58-1.41 (m, 4H),1.35 (t, J = 6.9 Hz, 3H), 0.87 (t, J = 6.9 Hz, 3H), 0.64 (t, J = 7.2 Hz,3H). 1096 192.1-196.2 405.1 *** *** ¹H NMR (DMSO-d₆, 300 Hz), δ 8.60 (s,1H), 7.58 (d, J = 8.4 Hz, 2H), 7.49-7.41 (m, 3H), 7.22 (s, 1H), 6.89(dd, J = 2.1 Hz and 6.6 Hz, 1H), 6.12 (d, J = 7.5 Hz, 1H), 4.15-4.06 (m,4H), 3.80-3.73 (m, 1H), 1.58-1.50 (m, 2H), 1.35 (t, J = 6.9 Hz, 3H),1.10 (d, J = 6.6 Hz, 6H), 0.64 (t, J = 7.2 Hz, 3H). 1097 196.4-202.3419.1 *** *** ¹H NMR (DMSO-d₆, 300 Hz), δ 8.72 (s, 1H), 7.59 (d, J = 8.4Hz, 2H), 7.49-7.41 (m, 3H), 7.22 (s, 1H), 6.89 (dd, J = 1.8 Hz and 6.9Hz, 1H), 6.24 (t, J = 5.4 Hz, 1H), 4.15-4.06 (m, 4H), 3.12-3.06 (m, 2H),1.58-1.51 (m, 2H), 1.44-1.21 (m, 7H), 0.89 (t, J = 7.2 Hz, 3H), 0.83 (t,J = 7.2 Hz, 3H). 1098 217.8-221.4 391.0 ** ¹H NMR (DMSO-d₆, 300 Hz), δ8.74 (s, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 1H), 7.38(d, J = 8.4 Hz, 2H), 7.20 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 2.1 Hz and6.6 Hz, 1H), 6.22 (t, J = 5.4 Hz, 1H), 4.62-4.53 (m, 1H), 4.11 (q, J =6.9 Hz, 2H), 3.16-3.07 (m, 2H), 1.52 (d, J = 6.6 Hz, 6H), 1.35 (t, J =6.9 Hz, 3H), 1.05 (t, J = 7.2 Hz, 3H). 1099 162.1-165.1 405.1 ** ¹H NMR(DMSO-d₆, 300 Hz), δ 8.73 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.49 (d, J= 8.1 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 2.1 Hz, 1H), 6.92(dd, J = 2.1 Hz and 6.6 Hz, 1H), 6.26 (t, J = 5.7 Hz, 1H), 4.62-4.53 (m,1H), 4.11 (q, J = 6.9 Hz, 2H), 3.09-3.02 (m, 2H), 1.52 (d, J = 6.6 Hz,6H), 1.48-1.41 (m, 2H), 1.35 (t, J = 6.9 Hz, 3H), 0.87 (t, J = 7.2 Hz,3H). 1100 228.6-231.4 405.1 *** ¹H NMR (DMSO-d₆, 300 Hz), δ 8.60 (s,1H), 7.57 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.7 Hz, 1H), 7.38 (d, J =8.7 Hz, 2H), 7.20 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 2.1 Hz and 6.6 Hz,1H), 6.11 (d, J = 7.8 Hz, 1H), 4.62-4.52 (m, 1H), 4.11 (q, J = 6.9 Hz,2H), 3.79-3.72 (m, 1H), 1.53-1.51 (m, 6H), 1.35 (t, J = 6.9 Hz, 3H),1.11-1.09 (m, 6H). 1101 157.2-160.5 419.1 *** (DMSO, 300 Hz), δ 8.72 (s,1H), 7.58 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 1H), 7.37 (d, J =8.4 Hz, 2H), 7.20 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 2.1 Hz and 6.6 Hz,1H), 6.23 (t, J = 5.7 Hz, 1H), 4.62-4.55 (m, 1H), 4.11 (q, J = 6.9 Hz,2H), 3.12-3.06 (m, 2H), 1.52 (d, J = 6.6 Hz, 6H), 1.47-1.21 (m, 7H),0.86 (t, J = 6.9 Hz, 3H). 1102 197.3-201.6 467.0 *** *** ¹H NMR (CD₃CN,300 Hz), δ 7.58-7.46 (m, 4H), 7.38 (d, J = 8.7 Hz, 2H), 7.30-7.15 (m,5H), 7.15 (s, 1H), 6.89 (dd, J = 2.1 Hz and 6.6 Hz, 1H), 5.31 (br, 1H),4.64-4.59 (m, 1H), 4.09 (q, J = 6.9 Hz, 2H), 3.44-3.42 (m, 2H), 2.80 (t,J = 6.6 Hz, 2H), 1.54 (d, J = 6.6 Hz, 6H), 1.38 (t, J = 6.9 Hz, 3H).1103 162-163 424.27 ** 1104 245-248 422.29 ** 1105 175-176 422.27 **1106 217-219 429.32 *** *** 1107 157-158 428.25 (M − H+) *** *** 1108213-215 435.28 *** *** 1109 155-156 444.31 *** *** 1110 191-195 425.2 **1111 180-183 406.2 ** 1112 173-175 463.2 ** 1113 151.155 495.4 ** 1114171-176 511.2 *** 1115 155-156 497.2 ** 1116 218-220 511.2 ** 1117106-109 509.2 ** 1118 126-130 462.2 ** 1119 184-186 405.31 ** 1120223-225 417.37 *** *** ¹H NMR (300 MHz, CDCl₃): 7.61 (1H, d, J = 9.2Hz), 7.51 (2H, d, J = 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz), 7.10 (2H, m),4.90 (2H, m), 4.13 (2H, q, J = 6.9 Hz), 3.97 (2H, d, J = 6.6 Hz), 1.47(3H, t, J = 7.0 Hz), 1.20 (6H, d, J = 8.6 Hz), 1.05 (1H, m), 0.43 (2H,m), 0.06 (2H, m) 1121 162-164 501.17 *** 1122 170-173 491.4 *** 112375-80 525.4 *** 1124 100-104 474.5 [M − H]⁻ *** ** 1125 188-190 488.4*** *** 1126 130-134 510.3 ** 1127 112-115 418.3 *** *** 1128 203-204432.3 *** *** 1129 115-116 432.3 *** *** 1130 177-178 386.26 ** ¹H NMR(300 MHz, DMSO-d₆): δ 10.02 (1H, s), 7.69 (2H, d, J = 8.8 Hz), 7.67 (1H,d, J = 8.5 Hz), 7.61 (1H, d, J = 2.0 Hz), 7.55 (2H, d, J = 8.8 Hz), 7.28(1H, t, J = 74.4 Hz), 7.13 (1H, dd, J = 8.5, 2.0 Hz), 4.20 (2H, q, J =7.3 Hz), 3.70 (3H, s), 1.18 (3H, t, J = 7.3 Hz). ¹⁹F NMR (300 MHz,DMSO-d₆): δ −81.95 (2F, d, J = 73.3 Hz). 1131 174-175 400.26 ** ¹H NMR(300 MHz, DMSO-d₆): δ 9.98 (1H, s), 7.69 (2H, d, J = 8.8 Hz), 7.67 (1H,d, J = 8.8 Hz), 7.61 (1H, d, J = 2.0 Hz), 7.54 (2H, d, J = 8.8 Hz), 7.28(1H, t, J = 74.4 Hz), 7.13 (1H, dd, J = 8.8, 2.0 Hz), 4.20 (2H, q, J =7.0 Hz), 4.15 (2H, q, J = 7.3 Hz), 1.26 (3H, t, J = 7.0 Hz), 1.18 (3H,t, J = 7.3 Hz). ¹⁹F NMR (300 MHz, DMSO-d₆): δ −81.95 (2F, d, J = 75.3Hz). 1132 148-149 414.25 ** ¹H NMR (300 MHz, DMSO-d₆): δ 9.99 (1H, s),7.70 (2H, d, J = 8.8 Hz), 7.67 (1H, d, J = 8.5 Hz), 7.61 (1H, d, J = 2.0Hz), 7.54 (2H, d, J = 8.8 Hz), 7.28 (1H, t, J = 74.4 Hz), 7.13 (1H, dd,J = 8.5, 2.0 Hz), 4.20 (2H, q, J = 7.0 Hz), 4.07 (2H, t, J = 6.7 Hz),1.65 (2H, hx, J = 7.6 Hz), 1.18 (3H, t, J = 7.2 Hz), 0.94 (3H, t, J =7.5 Hz). ¹⁹F NMR (300 MHz, DMSO-d₆): δ −81.96 (2F, d, J = 73.3 Hz). 1133139-140 428.25 ** ¹H NMR (300 MHz, DMSO-d₆): δ 9.98 (1H, s), 7.72-7.66(3H, m), 7.61 (1H, d, J = 2.0 Hz), 7.54 (2H, d, J = 8.8 Hz), 7.28 (1H,t, J = 74.4 Hz), 7.13 (1H, dd, J = 8.8, 2.0 Hz), 4.20 (2H, q, J = 7.3Hz), 4.11 (2H, t, J = 6.9hz), 1.66-1.56 (2H, m), 1.45-1.35 (2H, m), 1.18(3H, t, J = 7.3 Hz), 0.91 (3H, t, J = 7.3 Hz). ¹⁹F NMR (300 MHz,DMSO-d₆): δ −81.92 (2F, d, J = 73.3 Hz). 1134 142-143 426.30 (M − H+) **¹H NMR (300 MHz, DMSO-d₆): δ 9.99 (1H, s), 7.70 (2H, d, J = 8.8 Hz),7.67 (1H, d, J = 8.8 Hz), 7.61 (1H, d, J = 2.0 Hz), 7.54 (2H, d, J = 8.8Hz), 7.28 (1H, t, J = 74.4 Hz), 7.13 (1H, dd, J = 8.8, 2.0 Hz), 4.20(2H, q, J = 7.0 Hz), 3.90 (2H, d, J = 6.7 Hz), 1.93 (1H, m, J = 6.7 Hz),1.18 (3H, t, J = 7.0 Hz), 0.93 (6H, d, J = 6.7 Hz). ¹⁹F NMR (300 MHz,DMSO-d₆): δ −81.92 (2F, d, J = 73.3 Hz). 1135 144-145 412.24 *** ¹H NMR(300 MHz, DMSO-d₆): δ 10.10 (1H, s), 7.72-7.66 (3H, m), 7.62 (1H, d, J =2.0 Hz), 7.55 (2H, d, J = 8.8 Hz), 7.28 (1H, t, J = 74.4 Hz), 7.13 (1H,dd, J = 8.5, 2.0 Hz), 6.06-5.93 (1H, m), 5.41-5.22 (2H, m), 4.64 (2H,dt, J = 5.5, 1.3 Hz), 4.20 (2H, q, J = 7.3 Hz), 1.18 (3H, t, J = 7.3Hz). ¹⁹F NMR (300 MHz, DMSO-d₆): δ −81.92 (2F, d, J = 73.3 Hz). 1136172-174 413.25 ** ¹H NMR (300 MHz, DMSO-d₆): δ 8.77 (1H, s), 7.66 (1H,d, J = 8.8 Hz), 7.62 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.46(1H, d, J = 2.0 Hz), 7.27 (1H, t, J = 74.4 Hz), 7.13 (1H, dd, J = 8.8,2.0 Hz), 6.28 (1H, t, J = 5.7 Hz), 4.20 (2H, q, J = 7.3 Hz), 3.05 (2H,q, J = 6.2 Hz), 1.44 (2H, hx, J = 6.7 Hz), 1.19 (3H, t, J = 7.2 Hz),0.87 (3H, t, J = 7.5 Hz). ¹⁹F NMR (300 MHz, DMSO-d₆): δ −81.92 (2F, d, J= 73.3 Hz). 1137 180-182 413.26 ** ¹H NMR (300 MHz, DMSO-d₆): δ 8.65(1H, s), 7.66 (1H, d, J = 8.8 Hz), 7.61 (1H, d, J = 2.0 Hz), 7.60 (2H,d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.27 (1H, t, J = 74.4 Hz),7.13 (1H, dd, J = 8.8, 2.0 Hz), 6.14 (1H, d, J = 7.6 Hz), 4.20 (2H, q, J= 7.0 Hz), 3.77 (1H, m, J = 7.3 Hz), 1.18 (3H, t, J = 7.3 Hz), 1.10 (6H,d, J = 6.5 Hz). ¹⁹F NMR (300 MHz, DMSO-d₆): δ −81.92 (2F, d, J = 73.3Hz). 1138 146-149 427.27 ** ¹H NMR (300 MHz, DMSO-d₆): δ 8.76 (1H, s),7.66 (1H, d, J = 8.8 Hz), 7.62 (2H, d, J = 8.8 Hz), 7.61 (1H, d, J = 2.0Hz), 7.47 (2H, d, J = 8.8 Hz), 7.27 (1H, t, J = 74.4 Hz), 7.13 (1H, dd,J = 8.8, 2.0 Hz), 6.25 (1H, t, J = 5.7 Hz), 4.21 (2H, q, J = 7.3 Hz),3.09 (2H, q, J = 5.8 Hz), 1.47-1.25 (4H, m), 1.18 (3H, t, J = 7.0 Hz),0.89 (3H, t, J = 7.0 Hz). ¹⁹F NMR (300 MHz, DMSO-d₆): δ −81.92 (2F, d, J= 73.3 Hz). 1139 179-180 411.27 ** ¹H NMR (300 MHz, DMSO-d₆): δ 8.92(1H, s), 7.66 (1H, d, J = 8.8 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.61 (1H,d, J = 2.0 Hz), 7.48 (2H, d, J = 8.8 Hz), 7.28 (1H, t, J = 74.4 Hz),7.13 (1H, dd, J = 8.8, 2.0 Hz), 6.43 (1H, t, J = 5.8 Hz), 5.59-5.80 (1H,m), 5.22-5.07 (2H, m), 4.21 (2H, q, J = 7.3 Hz), 3.75 (2H, t, J = 6 Hz),1.19 (3H, t, J = 7.3 Hz). ¹⁹F NMR (300 MHz, DMSO- d₆): δ −81.92 (2F, d,J = 73.3 Hz). 1140 198-202 450.2 [M − H]⁻ ** 1141 156-160 448.2 [M − H]⁻** 1142 110-111 487.41 *** *** 1143 215-218 417.5 *** *** 1144 207-210429.5 *** *** 1145 205-208 445.2 ** 1146 187-191 430.32 *** *** 1147154-158 444.25 *** *** ¹H NMR (300 MHz, d₆-acetone): δ 8.92 (s, 1H),7.82 (d, 2H, J = 8.7 Hz), 7.62-7.49 (m, 3H), 7.30 (d, 1H, J = 2.1 Hz),6.98 (dd, 1H, J = 8.7, 2.1 Hz), 5.095 (pentet, 1H, J = 9.0 Hz), 4.32 (m,1H), 4.17 (q, 2H, J = 6.9 Hz), 2.7-2.8 (m, 2H), 2.35-2.5 (m, 2H),1.8-2.0 (m, 2H), 1.42 (t, 3H, J = 6.9 Hz), 1.34 (d, 3H, J = 6.3 Hz),1.0-1.1 (m, 1H), 0.6-0.8 (m, 3H), 0.5-0.59 (m, 1H) 1148 193-195 402.24(M − H+) *** *** 1149 158-159 416.37 (M − H+) *** *** 1150 173-175416.32 (M − H+) *** *** ¹H NMR (300 MHz, CDCl₃): δ 7.62 (1H, d, J = 9.3Hz), 7.58 (2H, d, J = 8.8 Hz), 7.46 (2H, d, J = 8.8 Hz), 7.10 (2H, m),6.77 (1H, s), 5.05 (1H, m), 4.13 (2H, q, J = 7.2 Hz), 3.97 (2H, d, J =6.6 Hz), 1.47 (3H, t, J = 6.9 Hz), 1.32 (6H, d, J = 6.0 Hz), 1.05 (1H,m), 0.43 (2H, m), 0.05 (2H, m) 1151 171-172 432.30 *** *** 1152 198-199444.31 (M − H+) *** *** 1153 154-155 466.28 *** *** 1154 207-208 444.31(M − H+) *** *** 1155 200-202 466.28 ** 1156 226-228 444.31 (M − H+) ****** 1157 199-201 466.28 *** *** 1158 173-179 442.27 (ES−) *** *** 1159206-208 (Weak *** *** ionization) 1160 193-194 422.3 *** ** 1161 183-185410.2 *** ** 1162 192-193 403.3 ** 1163 188-189 403.2 ** 1164 188-190417.2 *** * 1165 190-192 429.3 ** ** 1166 260-266 445.25 ** 1167 208-212430.25 *** *** 1168 218-221 (Weak *** *** ¹H NMR (300 MHz, d⁶-acetone):δ ionization) 8.08 (s, 1H), 7.69 (d, 2H, J = 8.7 Hz), 7.54 (d, 1H, J =8.7 Hz), 7.43 (d, 2H, J = 8.7 Hz), 7.30 (d, 1H, J = 2.1 Hz), 6.97 (dd,1H, J = 8.7, 2.1 Hz), 6.10 (d, 1H, J = 8.1 Hz), 5.08 (pentet, 1H, J =9.3 Hz), 4.32 (sextet, 1H, J = 8.1 Hz), 4.16 (q, 2H, J = 6.9 Hz),2.7-2.85 (m, 2H), 2.35 2.5 (m, 2H), 2.15-2.35 (m, 2H), 1.8 2.0 (m, 4H),1.6-1.7 (m 2H), 1.42 (t, 3H, J = 6.9 Hz) 1169 224-226 432.3 *** *** 1170180-181 469.3 ** 1171 219-220 431.2 *** *** 1172 198-199 431.33 *** ***1173 203-205 443.31 *** *** 1174 180-181 436.28 *** *** 1175 202-203456.27 *** *** 1176 170-172 390.2 ** 1177 145-147 404.2 *** ** 1178182-183 418.3 *** *** 1179 173-174 430.2 ** 1180 179-180 402.2 ** 1181179-180 424.2 ** 1182 162-163 422.2 *** * 1183 202.3-205.9 440.3 *** ¹HNMR (CD3CN, 300 MHz), δ 8.86 (s, 1H), 8.66 (s, 1H), 7.80 (d, J = 8.7 Hz,2H), 7.58-7.49 (m, 4H), 7.42 (s, 1H), 7.09 (d, J = 2.1 Hz, 1H), 6.95(dd, J = 2.1 Hz and 8.7 Hz, 1H), 4.58 (t, J = 4.8 Hz, 2H), 4.42 (t, J =4.8 Hz, 2H), 4.16 (q, J = 6.9 Hz, 2H), 1.76-1.67 (m, 1H), 1.25 (t, J =7.2 Hz, 3H), 0.95-0.89 (m, 4H). 1184 165.4-170.1 440.3 ** ¹H NMR (CD3CN,300 MHz), δ 8.81 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 2.1 Hz,1H), 7.54-7.49 (m, 4H), 7.02 (d, J = 2.1 Hz, 1H), 6.88 (dd, J = 2.1 Hzand 8.7 Hz, 1H), 6.30 (t, J = 1.8 Hz, 1H), 4.57 (t, J = 4.8 Hz, 2H),4.44 (t, J = 5.1 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 1.73-1.68 (m, 1H),1.24 (t, J = 7.2 Hz, 3H), 0.95-0.82 (m, 4H). 1185 211-213 454.30 *** ¹HNMR (300 MHz, DMSO-d₆): δ 8.76-8.70 (2H, m), 8.53 (1H, d, J = 4.7 Hz),7.91 (1H, d, J = 7.9 Hz), 7.60 (2H, d, J = 8.5 Hz), 7.51 (1H, d, J = 8.5Hz), 7.46-7.38 (8H, m), 7.00 (1H, dd, J = 8.5, 1.2 Hz), 6.27 (1H, t, J =5.6 Hz), 5.25 (2H, s), 4.18 (2H, q, J = 7.0 Hz), 3.05 (2H, q, J = 6.4Hz), 1.44 (2H, hx, J = 7.3 Hz), 1.17 (3H, t, J = 7.0 Hz), 0.87 (3H, t, J= 7.4 Hz). 1186  150. 464.34 (M − H+) ** ¹H NMR (300 MHz, DMSO-d₆): δ9.90 (1H, s), 7.67 (1H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.58(1H, d, J = 2.0 Hz), 7.48 (2H, d, J = 8.8 Hz), 7.29 (1H, t, J = 74.4Hz), 7.15 (1H, dd, J = 8.8, 2.0 Hz), 5.13-5.08 (1H, m), 4.99 (1H, p, J =8.5 Hz), 2.55-2.40 (2H, m), 2.37-2.24 (2H, m), 1.92-1.57 (10H, m). ¹⁹FNMR (300 MHz, DMSO-d₆): δ −82.08 (2F, d, J = 73.3 Hz). 1187 198-199439.29 ** ¹H NMR (300 MHz, DMSO-d₆): δ 8.76 (1H, s), 7.67 (1H, d, J =8.5 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.42 (2H,d, J = 8.8 Hz), 7.29 (1H, t, J = 74.4 Hz), 7.14 (1H, dd, J = 8.5, 2.0Hz), 6.28 (1H, t, J = 5.7 Hz), 5.00 (1H, p, J = 8.6 Hz), 3.05 (2H, q, J= 6.1 Hz), 2.59-2.42 (2H, m), 2.39-2.24 (2H, m), 1.84-1.66 (2H, m), 1.44(2H, hx, J = 7.0 Hz), 0.87 (3H, t, J = 7.4 Hz). ¹⁹F NMR (300 MHz,DMSO-d₆): δ −82.05 (2F, d, J = 73.3 Hz). 1188 222-223 474.25 ** ¹H NMR(300 MHz, DMSO-d₆): δ 10.26 (1H, s), 7.70 (1H, d, J = 8.8 Hz), 7.54 (2H,d, J = 8.8 Hz), 7.40 (1H, d, J = 2.0 Hz), 7.39 (2H, d, J = 8.8 Hz), 7.29(1H, t, J = 74.4 Hz), 7.16 (1H, dd, J = 8.8, 2.0 Hz), 4.71 (1H, p, J =9.1 Hz), 3.24-3.19 (2H, m), 2.22-1.60 (10H, m), 0.97 (3H, t, J = 7.4Hz). ¹⁹F NMR (300 MHz, DMSO-d₆): δ −82.05 (2F, d, J = 73.3 Hz). 1189183-158 472.24 *** *** ¹H NMR (300 MHz, DMSO-d₆): δ 10.24 (1H, s), 7.70(1H, d, J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz), 7.44 (2H, d, J = 8.8 Hz),7.40 (1H, d, J = 2.0 Hz), 7.30 (1H, t, J = 74.4 Hz), 7.16 (1H, dd, J =8.8, 2.0 Hz), 4.71 (1H, p, J = 9.1 Hz), 2.84-2.75 (1H, m), 2.20-1.84(6H, m), 1.65-1.60 (2H, m), 1.05-0.95 (2H, m), 0.60-0.49 (2H, m). ¹⁹FNMR (300 MHz, DMSO-d₆): δ −82.05 (2F, d, J = 75.3 Hz). 1190 185-186465.27 ** ¹H NMR (300 MHz, DMSO-d₆): δ 8.60 (1H, s), 7.67 (1H, d, J =8.8 Hz), 7.58 (1H, d, J = 1.9 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.42 (2H,d, J = 8.8 Hz), 7.29 (1H, t, J = 74.4 Hz), 7.14 (1H, dd, J = 8.8, 1.9Hz), 6.30 (1H, d, J = 7.3 Hz), 5.00 (1H, p, J = 8.6 Hz), 3.94 (1H, hx, J= 6.7 Hz), 2.60-2.40 (2H, m), 2.38-2.23 (2H, m), 1.90-1.34 (10H, m). ¹⁹FNMR (300 MHz, DMSO-d₆): δ −82.05 (2F, d, J = 75.3 Hz). 1191 216-219415.31 ** 1192 159-162 489.37 ** 1193 213-214 404.3 *** 1194 196-197418.3 *** *** 1195 114-115 418.3 *** *** 1196 124-125 416.3 *** *** 1197118-119 432.3 ** *** 1198 181-182 432.3 *** *** 1199 187-188 444.3 ****** 1200 188-189 446.3 *** *** 1201 182-183 466.3 *** *** 1202 195-197406.3 *** *** 1203 184-187 420.3 *** *** 1204 168-169 420.3 *** *** 1205155-157 445.3 *** *** 1206 178-180 434.3 *** *** 1207 204-205 448.3 ****** 1208 186-190 444.30 *** *** 1209 189-192 456.30 (ES−) *** *** 1210148-152 503.36 *** *** 1211 203-205 458.3 *** *** 1212 192-193 480.34*** *** 1213 192-193 480.33 *** *** 1214 170-173 457.3 *** *** 1215200-204 446.26 *** *** 1216 205-209 460.31 ** 1217 135-141 388.34 **1218 192-193 481.31 *** *** 1219 192-193 507.35 *** *** 1220 192-193481.28 *** *** 1221 222-225 431.3 *** *** 1222 191-192 446.35 ** 1223206-208 417.3 *** *** 1224 191-192 417.3 ** 1225 183-184 431.3 ** ***1226 189-190 443.3 *** *** 1227 168-169 479.3 *** *** 1228 174-175 423.5** 1229 163-164 438.3 ** 1230 179-180 436.3 ** 1231 189-191 424.2 **1232 184-185 404.2 *** ** 1233 192-193 430.4 *** *** 1234 204-205 390.1** 1235 209-211 410.1 ** 1236 196-197 404.14 *** *** 1237 150-151 432.1** 1238 176-177 458.4 ** 1239 187-193 360.35 *** *** 1240 168-170 460.38*** *** 1241 151-168 432.3 *** *** 1242 134-136 446.3 *** *** 1243161-163 446.3 *** *** 1244 145-147 446.3 *** *** 1245 245-246 318.3 **1246 157-163 434.4 *** *** 1247 188-190 432.4 *** *** 1248 207-210 462.4*** *** 1249 181-184 448.4 *** *** 1250 144-148 448.38 *** *** 1251137-142 (Weak ** ** ionization) 1252 131-134 446.37 ** 1253 224 517.3 **1254 189 498.6 *** *** ¹H NMR (300 MHz, DMSO-d₆): δ 9.89 (1H), 7.64(3H), 7.46 (3H), 7.19 (2H), 6.94 (1H), 6.87 (1H), 4.91 (2H), 4.19 (2H),4.01 (2H), 2.48 (2H), 2.21 (2H), 2.17 (2H), 1.71 (2H), 1.27 (6H) 1255208 499.4 *** *** ¹H NMR (300 MHz, DMSO-d₆): δ 9.91 (1H), 8.53 (1H),7.97 (1H), 7.65 (2H), 7.46 (3H), 7.19 (1H), 6.92 (1H), 4.95 (2H), 4.39(2H), 4.06 (2H), 2.48 (2H), 2.67 (4H), 1.72 (2H), 1.24 (6H). 1256188.4-191.3 467.1 *** ¹H NMR ( (CD₃CN, 300 Hz), δ 7.60 (d, J = 9.0 Hz,2H), 7.53 (d, J = 8.7 Hz, 1H), 7.47-7.23 (m, 7H), 7.04 (s, 1H), 6.91(dd, J = 2.1 Hz and 6.6 Hz, 1H), 5.31-5.27 (m, 1H), 4.16-4.07 (m, 4H),4.45 (q, J = 6.6 Hz, 2H), 2.83 (t, J = 6.6 Hz, 2H), 1.69-1.61 (m, 2H),1.41 (t, J = 6.9 Hz, 3H), 0.71 (t, J = 7.5 Hz, 3H). 1257 541.55 *** 1258527.55 *** 1259 526.57 *** 1260 208 503.5 *** 1261 156 530.5 *** 1262167 533.5 ** 1263 155-157 458.4 (ES−) *** 1264 177-180 467.40 *** 1265164-167 432.37 *** 1266 175-176 453.34 ** ¹H NMR (300 MHz, CDCl₃): δ7.70 (1H, d, J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.8Hz), 7.29 (1H, d, J = 1.8 Hz), 7.22 (1H, br s), 7.13 (1H, dd, J = 8.8,1.8 Hz), 6.81 (1H, t, J = 74.4 Hz), 4.02 (2H, d, J = 6.7 Hz), 3.82 (1H,hx, J = 6.4 Hz), 1.51 (2H, p, J = 7.1 Hz), 1.17 (3H, d, J = 6.7 Hz),1.07-0.99 (1H, m), 0.94 (3H, t, J = 7.4 Hz), 0.48-0.41 (2H, m),0.09-0.04 (2H, m). ¹⁹F NMR (300 MHz, CDCl₃): δ −80.81 (2F, d, J = 73.3Hz). 1267 139-140 466.06 ** ¹H NMR (300 MHz, CDCl₃): δ 7.72 (1H, d, J =8.8 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.28 (1H,d, J = 1.8 Hz), 7.12 (1H, dd, J = 8.8, 1.8 Hz), 6.79 (1H, br s), 6.56(1H, t, J = 74.4 Hz), 4.35 (1H, dq, J = 8.6, 6.7 Hz), 4.02 (2H, d, J =6.7 Hz), 1.39 (3H, d, J = 6.7 Hz), 1.11-0.99 (2H, m), 0.64-0.43 (5H, m),0.34-0.28 (1H, m), 0.09-0.04 (2H, m). ¹⁹F NMR (300 MHz, CDCl₃): δ −80.75(2F, d, J = 75.3 Hz). 1268 145-146 454.30 ** ¹H NMR (300 MHz, CDCl₃): δ7.73 (1H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8Hz), 7.28 (1H, d, J = 1.8 Hz), 7.12 (1H, t, J = 8.5, 1.8 Hz), 6.76 (1H,br s), 6.56 (1H, t, J = 74.4 Hz), 4.89 (1H, hx, J = 6.4 Hz), 4.02 (2H,d, J = 6.7 Hz), 1.74-1.59 (2H, m), 1.30 (3H, d, J = 6.1 Hz), 1.11-1.00(1H, m), 0.97 (3H, t, J = 7.4 Hz), 0.49-0.43 (2H, m), 0.09-0.04 (2H, m).¹⁹F NMR (300 MHz, CDCl₃): δ −80.75 (2F, d, J = 73.3 Hz). 1269 112 461.4*** 1270 158 475.5 *** 1271 192 503.5 *** 1272 199 515.6 *** 1273 212519.5 ** 1274 139 505.5 *** 1275 115 484.5 *** 1276 214 485.4 *** 1277208 473.5 *** 1278 181 489.5 *** 1279 205-207 473.43 *** 1280 175-176490.35 (M − H+) *** 1281 168-169 500.47 *** 1282 196-197 486.43 *** 1283169-170 486.42 (M − H+) *** 1284 154-155 498.31 (M − H+) *** 1285168-170 472.39 (M − H+) *** 1286 161-163 486.43 *** 1287 141-143 498.27(M − H+) *** 1288 211-213 485.42 *** 1289 178-185 478.32 (ES−) *** 1290172-174 444.39 (ES−) *** 1291 177-178 430.4 *** 1292 202-203 430.4 ***1293 193-194 430.4 *** 1294 155-157 444.4 *** 1295 174-175 444.4 ***1296 170-171 444.4 ** 1297 163-165 446.4 ** 1298 178-180 446.4 ** 1299150-152 448.4 ** 1300 201-203 432.31 *** 1301 216-218 431.37 *** 1302226-227 417.4 ** 1303 215-216 417.3 ** 1304 209-211 415.3 ** 1305 443.4*** 1306 155-160 516.5 ** 1307 115-119 529.5 ** 1308 109-110 497.7 ***1309 210-212 500.6 *** 1310 129-131 374.4 ** 1311 205-207 346.4 *** 1312180-185 458.43 (ES−) *** 1313 155-160 448.07 *** 1314 88-90 498.5 ***1315 125-130 502.5 ** 1316 110-112 472.5 *** 1317 122-125 472.5 *** 1318130-134 484.5 *** 1319 108-113 460.5 *** 1320  98-101 474.5 *** 132183-87 504.6 ** 1322 112-115 483.5 *** 1323 148-150 432.4 *** 1324227-229 433.4 *** 1325 195-198 417.4 *** 1326 246-248 431.4 ** 1327  93487.5 *** 1328 162 510.5 *** 1329  98 511.4 *** Compound Melting MassSpec Replicon IC₅₀ Number Point (° C.) [M + H] μM 3-day ¹H NMR Data 2129175-180 472.4 (M − 1) *** 2130 180-182 450.2 *** 2131 521.1 * 2132541.2 * 2133 221-227 445.4 *** 2134 185-190 446.4 *** 2135 180-185 444.3(M − 1) *** 2136 135-137 404.2 ** ¹H NMR (CDCl₃, 300 MHz), δ 7.57 (d, J= 8.7 Hz, 2H), 7.47 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 6.6 Hz, 1H), 7.18(d, J = 1.5 Hz, 1H), 6.97 (dd, J = 6.6 Hz and 1.5 Hz, 1H), 6.73 (s, 1H),5.09-5.03 (m, 1H), 4.01 (d, J = 4.8 Hz, 2H), 3.90 (s, 3H), 1.33 (d, J =4.8 Hz, 6H), 1.07-1.04 (m, 1H), 0.43 (q, J = 6.9 Hz, 2H), 0.07 (q, J =3.6 Hz, 2H). 2137 176-177 440.1 (M + Na) ** ¹H NMR (CDCl₃, 300 MHz), δ7.54 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 9.0 Hz,1H), 7.18 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 6.6 Hz and 1.5 Hz, 1H),6.73 (s, 1H), 4.01 (d, J = 6.6 Hz, 2H), 3.89 (s, 3H), 1.55 (s, 9H),1.07-1.02 (m, 1H), 0.43 (q, J = 6.9 Hz, 2H), 0.05 (q, J = 3.6 Hz, 2H).2138 181-182 418.1 *** ¹H NMR (CDCl₃, 300 MHz), δ 7.56 (d, J = 8.7 Hz,2H), 7.46 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 9.0 Hz, 1H), 7.17 (d, J =2.4 Hz, 1H), 6.97 (dd, J = 9.0 Hz and 2.1 Hz, 1H), 6.72 (s, 1H),5.07-5.03 (m, 1H), 4.11 (q, J = 6.9 Hz, 2H), 4.00 (d, J = 6.6 Hz, 2H),1.46 (t, J = 7.2 Hz, 3H), 1.32 (d, J = 6.3 Hz, 6H), 1.09-1.01 (m, 1H),0.48-0.40 (m, 2H), 0.08-0.01 (m, 2H). 2139  185-186. 417.1 * ¹H NMR(DMSO, 400 MHz), δ 8.77 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.59 (d, J =8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 2.0 Hz, 1H), 6.94(dd, J = 9.2 Hz and 2.4 Hz, 1H), 6.30 (t, J = 8.8 Hz, 1H), 4.10-4.07 (m,4H), 3.05 (q, J = 6.8 Hz, 2H), 1.47-1.43 (m, 2H), 1.37 (t, J = 6.8 Hz,3H), 0.89-0.85 (m, 4H), 0.31-0.27 (m, 2H), 0.04-0.00 (m, 2H). 2140169-170 392.3 * ¹H NMR (CDCl₃, 400 MHz), δ 7.58-7.51 (m, 3H), 7.43 (d, J= 8.4 Hz, 2H), 7.18 (d, J = 2.4 Hz, 1H), 6.93 (dd, J = 9.2 Hz and 2.4Hz, 1H), 6.72 (s, 1H), 5.09-5.03 (m, 1H), 4.69-4.62 (m, 1H), 3.89 (s,3H), 1.59 (d, J = 7.2 Hz, 6H), 1.33 (d, J = 6.0 Hz, 6H). 2141 201-202398.2 ** ¹H NMR (CDCl₃, 300 MHz), δ 7.52 (dd, J = 8.7 Hz and 2.1 Hz,2H), 7.37 (dd, J = 7.2 Hz and 1.8 Hz, 2H), 7.32 (d, J = 9.0 Hz, 1H),7.17 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 9.0 Hz and J = 2.4 Hz, 1H), 6.81(s, 1H), 4.18-4.08 (m, 4H), 3.25 (q, J = 7.5 Hz, 2H), 1.49-1.42 (m, 6H),1.36 (t, J = 7.2 Hz, 3H). 2142 164-165 412.2 ** ¹H NMR (CDCl₃, 300 MHz),δ 7.52 (d, J = 8.1 Hz, 2H), 7.47-7.38 (m, 3H), 7.18 (s, 1H), 6.98 (d, J= 9.0 Hz, 1H), 6.90 (s, 1H), 4.19-4.04 (m, 4H), 3.23 (t, J = 7.2 Hz,2H), 1.99-1.83 (m, 2H), 1.46 (t, J = 6.6 Hz, 3H), 1.36 (t, J = 7.2 Hz,3H), 1.06 (t, J = 7.2 Hz, 3H). 2143 204-205 410.0 ** ¹H NMR (CDCl₃, 400MHz), δ 7.52 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 7.33 (d, J =9.0 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.03 (s, 1H), 6.99 (dd, J = 9.0Hz and 2.4 Hz, 1H), 4.19-4.08 (m, 4H), 2.66-2.27 (m, 1H), 1.46 (t, J =6.9 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H), 1.27-1.23 (m, 2H), 1.08-1.03 (m,2H). 2144 167-169 403.3 * ¹H NMR (CDCl₃, 400 MHz), δ 7.70 (br, 1H), 7.52(d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.8 Hz, 1H),7.17 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 9.2 Hz and 2.4 Hz, 1H), 4.12 (q,J = 7.2 Hz, 2H), 4.01 (d, J = 6.4 Hz, 2H), 3.37 (q, J = 6.8 Hz, 2H),1.47 (t, J = 6.8 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H), 1.10-1.04 (m, 1H),0.45 (q, J = 4.2 Hz, 2H), 0.09-0.03 (m, 2H). 2145 189-192 417.3 ** ¹HNMR (CDCl₃, 400 MHz), δ 7.50-7.43 (m, 4H), 7.38 (d, J = 9.2 Hz, 1H),7.22 (s, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 9.2 Hz and 2.4 Hz,1H), 4.12 (q, J = 6.8 Hz, 2H), 4.04-3.97 (m, 3H), 1.47 (t, J = 7.2 Hz,3H), 1.21 (d, J = 6.4 Hz, 6H), 1.06-1.04 (m, 1H), 0.42 (q, J = 6.4 Hz,2H), 0.06 (q, J = 4.8 Hz, 2H). 2146 162-163 406.3 * ¹H NMR (CDCl₃, 400MHz), δ 7.57-7.44 (m, 4H), 7.18-7.17 (m, 2H), 6.94 (dd, J = 9.2 Hz and2.4 Hz, 1H), 6.70 (s, 1H), 5.06-5.00 (m, 1H), 4.73-4.66 (m, 1H), 4.11(q, J = 6.8 Hz, 2H), 1.61 (d, J = 6.8 Hz, 6H), 1.46 (t, J = 7.2 Hz, 3H),1.31 (d, J = 6.4 Hz, 6H). 2147 182-184 360.2 *** 2148 142-146 416.4 ***2149 134-136 346.4 *** 2151 202-204 468.1 *** ¹H NMR (CDCl₃, 400 MHz), δ1.33 (d, 6H), 1.73-1.95 (m, 2H), 2.26-2.38 (m, 2H), 2.71-2.85 (m, 2H),4.90-5.10 (m, 2H), 6.72 (s, br, 1H), 7.08 (t, 1H), 7.14-7.18 (dd, 1H),7.43 (d, 2H), 7.56 (s, 1H), 7.59 (t, 2H), 7.79 (d, 1H), 8.60 (d, 2H)2152 164-168 393.3 *** 2153 207-211 392.3 *** 2154 185-195 470.3 (M − 1)*** 2155 194-195 378.2 ** ¹H NMR (CDCl₃, 300 MHz), δ 7.57 (d, J = 8.4Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 9.0 Hz, 1H), 7.17 (d, J= 1.8 Hz, 1H), 6.99 (dd, J = 9.0 Hz and 1.8 Hz, 1H), 6.76 (s, 1H), 4.26δ q, J = 6.9 Hz, 2H δ, 4.19-4.07 (m, 4H), 1.46 (t, J = 6.9 Hz, 3H),1.37-1.32 (m, 6H). 2156 179-180 392.1 ** ¹H NMR (CDCl₃, 300 MHz), δ 7.57(d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 9.0 Hz, 1H),7.17 (d, J = 2.1 Hz, 1H), 6.97 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 6.71 (s,1H), 5.07-5.03 δ m, 1H δ, 4.19-4.07 (m, 4H), 1.46 (t, J = 6.9 Hz, 3H),1.37-1.32 (m, 9H). 2157 223-224 377.2 * ¹H NMR (CDCl₃, 400 MHz), δ 7.52(d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 9.2 Hz, 1H),7.17-7.13 (m, 2H), 6.98 (dd, J = 8.8 Hz and 2.4 Hz, 1H), 5.10 (br, 1H),4.17-410 (m 4H), 3.32 δ q, J = 7.2 Hz, 2H δ, 1.47 (t, J = 7.2 Hz, 3H),1.34 (t, J = 7.2 Hz, 3H) 1.20 (t, J = 7.2 Hz, 3H). 2158 193-194 391.2 **¹H NMR (CDCl₃, 300 MHz), δ 7.72 (br, 1H), 7.52-7.42 (m, 4H), 7.33 (d, J= 9.0 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.7 Hz and 2.1Hz, 1H), 4.18-4.08 (m, 4H), 4.06-3.97 δ m, 1H δ, 1.47 (t, J = 6.9 Hz,3H), 1.35 (t, J = 7.2 Hz, 3H), 1.23 (d, J = 6.6 Hz, 6H). 2159 199-200405.3 * ¹H NMR (CDCl₃, 400 MHz), δ 7.54-7.52 (m, 3H), 7.37 (d, J = 8.4Hz, 2H), 7.30 (s, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.8 Hzand 2.4 Hz, 1H), 5.25 (br, 1H), 4.72-4.65 (m, 1H), 4.11 δ q, J = 6.8 Hz,2H δ, 3.24 (t, J = 7.2 Hz, 2H), 1.62-1.52 (m, 8H), 1.47 (t, J = 7.2 Hz,3H), 0.95 (t, J = 7.6 Hz, 3H). 2160 226-227 404.3 ** ¹H NMR (CDCl₃, 300MHz), δ 7.57 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 7.37 (d, J =9.0 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 9.0 Hz and 2.4 Hz,1H), 6.75 (s, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H),4.00 (d, J = 6.6 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 6.9 Hz,3H), 1.09-1.01 (m, 1H), 0.47-0.40 (m, 2H), 0.08-0.01 (m, 2H). 2161177-183 456.3 (M − 1) *** 2162 210-212 504.3 *** 2163 136-138 505.3 ***2164 160-164 442.3 (M − 1) *** 2165 179-180 406.2 ** ¹H NMR (DMSO, 400MHz), δ 9.69 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.8 Hz,1H), 7.49 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 2.0 Hz, 1H), 6.94 (dd, J =8.8 Hz and 2.4 Hz, 1H), 4.16 (q, J = 6.4 Hz, 2H), 4.07 δ q, J = 6.8 Hz,2H δ, 1.49 (s, 9H), 1.34 (t, J = 6.8 Hz, 3H), 1.18 (t, J = 6.8 Hz, 3H).2166 181-182 430.1 ** ¹H NMR (CDCl₃, 300 MHz), δ 7.54 (d, J = 8.4 Hz,2H), 7.46 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 9.0 Hz, 1H), 7.17 (d, J =2.7 Hz, 1H), 6.97 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.65 (s, 1H), 4.11(q, J = 6.9 Hz, 2H), 3.99 (d, J = 6.6 Hz, 2H), 1.55 (s, 9H), 1.46 (t, J= 6.9 Hz, 3H), 1.08-1.01 (m, 1H), 0.47-0.40 (m, 2H), 0.09-0.02 (m, 2H).2167 185-187 538.3 *** 2168 148-149 539.4 *** 2169 197-198 555.4 ***2170 141-143 513.4 *** 2171 202-204 429.3 *** 2172 179-183 421.3 ** 2173190-194 420.3 ** 2174 161-166 442.3 (M − 1) *** 2175 193-195 502.3 ***2176 187-189 502.3 *** 2177 167-196 476.3 *** 2178 235-237 530.3 ***2179 195-197 504.4 *** 2180 203-205 488.3 *** 2181 207-209 530.4 (M − 1)*** 2182 202-204 494.3 *** 2183 225-227 474.9 *** 2184 220-222 503.4 ***2185 212-215 487.4 *** 2187 >250. (decomposed) 395.8 ** ¹H NMR (CDCl₃,400 MHz), δ 8.08 (d, J = 7.6 Hz, 2H), 7.67-7.65 (m, 3H), 7.19 (s, 1H),6.99 (d, J = 8.8 Hz, 1H), 4.94-4.88 (m, 3H), 4.14 (q, J = 6.8 Hz, 2H),2.80-2.72 (m, 2H), 2.40-2.35 (m, 2H), 2.01-1.83 (m, 2H), 1.50 (t, J =6.8 Hz, 3H). 2188 210-212 437.9 ** ¹H NMR (CDCl₃, 400 MHz), δ 8.03 (d, J= 8.4 Hz, 2H), 7.67-7.63 (m, 3H), 7.18 (d, J = 1.6 Hz, 1H), 6.99 (dd, J= 8.8 Hz and 2.0 Hz, 1H), 4.91-4.87 (m, 1H), 4.35 (d, J = 7.6 Hz, 1H),4.14 (q, J = 6.8 Hz, 2H), 3.61-3.56 (m, 1H), 2.77-2.72 (m, 2H),2.38-2.32 (m, 2H), 1.96-1.82 (m, 2H), 1.49 (t, J = 7.2 Hz, 3H), 1.16 (d,J = 6.8 Hz, 6H). 2189 170-171 438.0 ** ¹H NMR (CDCl₃, 400 MHz), δ 8.01(d, J = 8.0 Hz, 2H), 7.67-7.63 (m, 3H), 7.18 (s, 1H), 6.99 (d, J = 8.8Hz, 1H), 4.94-4.85 (m, 1H), 4.45 (t, J = 6.4 Hz, 1H), 4.14 (q, J = 7.2Hz, 2H), 3.03 (q, J = 6.4 Hz, 2H), 2.81-2.70 (m, 2H), 2.39-2.32 (m, 2H),1.99-1.80 (m, 2H), 1.62-1.54 (m, 2H), 1.49 (t, J = 7.2 Hz, 3H), 0.95 (t,J = 7.2 Hz, 3H). 2190 191-193 451.9 * ¹H NMR (CDCl₃, 400 MHz), δ 8.03(d, J = 8.4 Hz, 2H), 7.67-7.63 (m, 3H), 7.17 (d, J = 1.6 Hz, 1H), 6.98(dd, J = 8.8 Hz and 2.0 Hz, 1H), 4.93-4.85 (m, 1H), 4.31 (d, J = 8.4 Hz,1H), 4.13 (q, J = 7.2 Hz, 2H), 3.40-3.33 (m, 1H), 2.78-2.68 (m, 2H),2.38-2.32 (m, 2H), 2.01-1.81 (m, 2H), 1.57-1.42 (m, 5H), 1.12 (d, J =7.2 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H). 2191 185-187 450.0 ** ¹H NMR(CDCl₃, 400 MHz), δ 8.00 (d, J = 8.0 Hz, 2H), 7.67-7.62 (m, 3H), 7.17(d, J = 1.6 Hz, 1H), 6.99 (dd, J = 8.8 Hz and 2.0 Hz, 1H), 4.91-4.84 (m,1H), 4.69 (d, J = 8.8 Hz, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.92-3.86 (m,1H), 2.79-2.69 (m, 2H), 2.38-2.32 (m, 2H), 2.26-2.18 (m, 2H), 1.98-1.82(m, 4H), 1.80-1.61 (m, 4H), 1.50 (t, J = 7.2 Hz, 3H). 2192 463.9 * ¹HNMR (CDCl₃, 400 MHz), δ 8.00 (d, J = 8.0 Hz, 2H), 7.67-7.63 (m, 3H),7.18 (s, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.94-4.85 (m, 1H), 4.45 (d, J =6.8 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.72-3.67 (m, 1H), 2.80-2.70 (m,2H), 2.38-2.32 (m, 2H), 1.98-1.80 (m, 4H), 1.65-1.43 (m, 9H). 2193218-221 410.2 * ¹H NMR (CDCl₃, 400 MHz), δ 8.02 (d, J = 8.4 Hz, 2H),7.67-7.59 (m, 3H), 7.19 (d, J = 2.0 Hz, 1H), 7.00 (dd, J = 8.8 Hz and2.0 Hz, 1H), 4.94-4.85 (m, 1H), 4.40-4.37 (q, J = 5.2 Hz, 1H), 4.14 (q,J = 6.8 Hz, 2H), 2.82-2.73 (m, 5H), 2.36 (q, J = 8.4, 2H), 2.01-1.83 (m,2H), 1.57 (t, J = 7.2 Hz, 3H). 2195 203-210 431.3 *** 2196 203-210 431.3*** 2197 180-182 525.46 *** 2198 197-200 524.37 *** 2199 160-163 511.44*** 2200 196-198 510.43 *** 2201 146-147 486.4 *** 2202 152-153 474.4*** 2203 215-216 485.4 *** 2204 164-165 500.4 *** 2205 179-181 510.4 (M− 1) *** ¹H NMR (300 MHz, CDCl₃): □ 7.62 (1H, d, J = 8.8 Hz), 7.58 (2H,d, J = 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz), 7.20 (1H, d, J = 2.0 Hz), 6.95(1H, dd, J = 8.8, 2.0 Hz), 6.81 (1H, br s), 4.94 (1H, p, J = 8.7 Hz),4.40 (1H, q, J = 0.7 Hz), 4.13 (2H, q, J = 7.0 Hz), 2.89-2.76 (2H, m),2.39-2.28 (2H, m), 2.00-1.50 (7H, m), 1.25-1.12 (2H, m), 1.17 (3H, s),1.12 (3H, s), 0.88 (3H, s). 2206 138-139 529 *** ¹H NMR (300 MHz,CDCl₃): □ 7.63 (1H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.43 (2H,d, J = 8.5 Hz), 7.20 (1H, d, J = 2.0 Hz), 6.95 (1H, dd, J = 8.8, 2.0Hz), 6.76 (1H, br s), 5.11 (1H, p, J = 5.1 Hz), 4.94 (1H, p, J = 8.5Hz), 4.13 (2H, q, J = 7.0 Hz), 2.90-1.65 (7H, m), 1.48 (3H, t, J = 7.0Hz), 1.25 (3H, s), 1.17 (3H, d, J = 7.6 Hz), 1.00 (3H, s). 2207 166-168510.4 ** ¹H NMR (300 MHz, CDCl₃): □ 7.62 (1H, d, J = 8.8 Hz), 7.57 (2H,d, J = 8.5 Hz), 7.50 (2H, d, J = 8.5 Hz), 7.20 (1H, d, J = 2.0 Hz), 6.95(1H, dd, J = 8.8, 2.0 Hz), 6.83 (1H, br s), 4.96 (1H, narrow m), 4.13(2H, q, J = 7.0 Hz), 2.88-2.77 (2H, m), 2.40-2.29 (2H, m), 2.17-1.50(19H, m). 2208 foam 482.1 *** 2209 foam 482.1 *** 2210 194-196 494.4 ***¹H NMR (300 MHz, CDCl₃): □0.27-0.37 (m, 1H), 0.44-0.65 (m, 3H),0.98-1.11 (m, 1H), 1.40 (d, 3H), 1.69-1.97 (m, 2H), 2.25-2.38 (m, 2H),2.69-2.87 (m, 2H), 4.29-4.41 (m, 1H), 4.88-5.04 (m, 1H), 6.76 (s, br,1H), 7.07 (t, 1H), 7.14-7.19 (dd, 1H), 7.40-7.46 (m, 2H), 7.53-7.62 (m,3H), 7.79 (d, 1H), 8.59 (d, 2H) 2211 119-120 510.4 *** 2212 151-153448.4 *** 2213 202-204 472.4 *** 2214 213-215 472.4 *** 2215 80-82 486.4*** 2216 498.4 *** 2217 154-156 480.1 *** ¹H NMR (300 MHz, CDCl₃):□0.26-0.35 (m, 1H), 0.44-0.73 (m, 5H), 0.96-1.10 (m, 3H), 1.40 (d, 3H),3.36-3.45 (m, 1H), 4.30-4.41 (m, 1H), 6.77 (s, br, 1H), 7.06 (t, 1H),7.13-7.17 (dd, 1H), 7.51 (d, 1H), 7.56-7.64 (q, 4H), 7.76 (d, 1H), 8.59(d, 2H) 2218 233-235 446.1 ** 2219 241-244 460.2 *** 2220 189-192 474.2*** 2221 218-220 474.2 *** 2222 145 472.2 *** (decomp.) 2223 195-197434.2 (M − 1) *** ¹H NMR (CDCl₃, 300 MHz), δ 8.06 (d, J = 8.4 Hz, 2H),7.68-7.65 (m, 3H), 7.18 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.4 Hz and1.8 Hz, 1H), 4.93-4.87 (m, 2H), 4.18-4.11 (m, 2H), 2.79-2.71 (m, 2H),2.41-2.35 (m, 3H), 1.97-1.82 (m, 2H), 1.49 (t, J = 6.9 Hz, 3H),0.71-0.68 (m, 4H). 2224 161-163 480.2 *** 2225 174-175 494.2 *** 2226163-164 494.2 *** 2227 174-176 492.2 *** 2228 208-210 492.2 ** 2229192-195 460.2 *** 2230 220-222 474.2 *** 2231 259-261 488.2 *** 2232178-180 488.2 *** 2233 239-240 486.2 *** 2234 120-123 488.3 *** 2235140-147 423.2 (M − 1) ** 2236 glass 516.5 (M − 1) *** 2237 178-179 504.2*** 2238 glass 536.4 (M − 1) *** 2239 209-211 454.5 *** 2240 91-93 482.5*** 2241 122-124 470.4 ** 2242 186-188 466.4 *** 2243 161-163 480.4 ***2244 178-180 416.2 ** ¹H NMR (CDCl₃, 400 MHz), δ 7.65 (d, J = 8.4 Hz,1H), 7.55-7.52 (m, 4H), 7.24 (d, J = 1.6 Hz, 1H), 6.98 (dd, J = 8.8 Hzand 2.0 Hz, 1H), 4.94-4.89 (m, 1H), 4.14 (q, J = 6.8 Hz, 2H), 3.59 (b,2H), 3.34 (b, 2H), 2.88-2.83 (m, 2H), 2.36-2.29 (m, 2H), 1.97-1.80 (m,2H), 1.49 (t, J = 6.8 Hz, 3H), 1.43-1.18 (m, 6H). 2245 235-236 402.1 **¹H NMR (CDCl₃, 400 MHz), δ 7.90 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.8Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.19 (s, 1H), 6.97 (dd, J = 8.8 Hzand 2.0 Hz, 1H), 5.97 (d, J = 7.6 Hz, 1H), 4.94-4.90 (m, 1H), 4.35-4.30(m, 1H), 4.13 (q, J = 6.8 Hz, 2H), 2.80-2.74 (m, 2H), 2.37-2.33 (m, 2H),1.95-1.79 (m, 2H), 1.49 (t, J = 6.8 Hz, 3H), 1.30 (d, J = 6.8 Hz, 6H).2246 201-202 ** ¹H NMR (CDCl₃, 300 MHz), δ 7.65 (d, J = 8.7 Hz, 1H),7.59-7.52 (m, 4H), 7.23 (d, J = 2.1 Hz, 1H), 6.98 (dd, J = 8.7 Hz and2.1 Hz, 1H), 4.94-4.88 (m, 1H), 4.14 (q, J = 6.9 Hz, 2H), 3.79-3.54 (m,8H), 2.88-2.80 (m, 2H), 2.37-2.29 (m, 2H), 1.98-1.80 (m, 2H), 1.49 (t, J= 6.9 Hz, 3H). 2247 154-156 400.2 ** ¹H NMR (CDCl₃, 400 MHz), δ 7.77 (d,J = 8.0 Hz, 2H), 7.65 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H),7.19 (d, J = 1.6 Hz, 1H), 6.98 (dd, J = 8.8 Hz and 2.0 Hz, 1H),4.93-4.88 (m, 1H), 4.33 (t, J = 6.8 Hz, 4H), 4.14 (q, J = 6.8 Hz, 2H),2.82-2.76 (m, 2H), 2.44-2.30 (m, 4H), 1.95-1.80 (m, 2H), 1.49 (t, J =6.8 Hz, 3H). 2248 217-218 414.2 ** ¹H NMR (CDCl₃, 400 MHz), δ 7.89 (d, J= 8.0 Hz, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.19(d, J = 1.6 Hz, 1H), 6.97 (dd, J = 8.4 Hz and 2.0 Hz, 1H), 6.29 (d, J =7.6 Hz, 1H), 4.94-4.89 (m, 1H), 4.64-4.62 (m, 1H), 4.13 (q, J = 6.8 Hz,2H), 2.80-2.74 (m, 2H), 2.48-2.47 (m, 2H), 2.38-2.31 (m, 2H), 2.02-1.78(m, 6H) 1.49 (t, J = 6.8 Hz, 3H). 2252 105-109 419.9 *** 2253 261-265304.6 ** 2254 204 515.3 *** (decomp.) 2255 228-231 426.2 *** 2256  194-196.5 440.3 ** 2257   208-210.5 438.3 *** 2258   182-187.5 440.3** 2259 62-65 456.3 *** 2260 155-157 486.3 *** 2261 glass 494.4 ** 2262glass 496.4 *** 2263 223-224 503.4 *** ¹H NMR (300 MHz, CDCl₃): □1.15(d, 6H), 1.70-1.92 (m, 2H), 2.31-2.45 (m, 2H), 2.64-2.81 (m, 2H),3.52-3.63 (m, 1H), 5.05-5.16 (m, 1H), 6.62 (d, 1H), 7.15-7.25 (m, 2H),7.47-7.52 (m, 2H), 7.56-7.61 (m, 2H), 7.70-7.75 (m, 2H), 8.562 (d, 2H),9.03 (s, br, 1H) 2264 196-201 373.0 * 2265 168-173 443.5 * 2266 218-223473.5 ** 2267 206-211 465.5 ** 2268 172-178 485 *** 2269 442.3 *** 2270228-233 484.2 *** 2278 glass 496.1 *** 2279 200-205 494.1 * 2280 155-160458.5 *** 2281 180-185 456.5 * 2282 181-185 470.5 *** 2283 198-203 459.5*** 2284 glass 514.2 (M − 1) *** 2285 glass 518.2 *** 2286 191-193 389.0*** 2287 glass 488.3 *** 2288 216-217 475.4 *** 2289 145-150 490.5 *2290 195-200 490.5 * 2291 240-245 470.5 *** 2292 195-196 475.1 ** 2298172-177 496.5 *** 2299 146-148 539.4 *** 2300 186-189 484.6 ** 2301241-243 481.5 *** 2302 197-202 467.4 ** 2303 414.3 * ¹H NMR (CDCl₃, 300MHz), δ 7.69-7.64 (m, 3H), 7.52 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 2.1Hz, 1H), 6.97 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.94-4.88 (m, 1H), 4.14(q, J = 6.9 Hz, 2H), 2.73-3.50 (m, 4H), 2.87-2.79 (m, 2H), 2.35-2.32 (m,2H), 1.97-1.83 (m, 6H), 1.49 (t, J = 6.9 Hz, 3H). 2304 428.2 ** ¹H NMR(CDCl₃, 300 MHz), δ 7.65 (d, J = 8.7 Hz, 1H), 7.57-7.50 (m, 4H), 7.23(d, J = 2.1 Hz, 1H), 6.98 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.91-4.88 (m,1H), 4.14 (q, J = 7.2 Hz, 2H), 3.75 (b, 2H), 3.43 (b, 2H), 2.88-2.81 (m,2H), 2.34-2.30 (m, 2H), 1.97-1.58 (m, 8H), 1.49 (t, J = 6.9 Hz, 3H).2305 glass 516.4 (M − 1) *** 2306 glass 536.4 (M − 1) *** 2307 509.3 **2308 78-80 444.4 (M − 1) *** 2309 217-222 470.5 *** 2310 178-183 496.5*** 2311 172-175 468.2 * 2313 glass 502.3 (M − 1) *** 2314 glass 488.4*** 2315 glass 488.5 *** 2316 glass 502.4 *** 2317 glass 474.8 *** 2318199-201 500.1 (M − 1) *** 2319 186 503.2 *** (decomp.) 2320 134 503.2*** (deomp.) 2321 234-235 489.2 *** 2322 187-189 480.3 *** 2323 247-250470.3 *** 2324 224-226 497.4 *** 2325 203-207 510 *** 2326 142-144 462.4*** 2327 153-155 496.4 (M − 1) *** 2328 74-80 466.1 *** 2329 78-84 500.0(M − 1) * 2330 160-163 480.2 *** 2331 188-192 472.1 *** 2332 180-184486.2 * 2333 198-202 460.2 ** 2334 199-203 474.1 *** 2335 208-212 472.1*** 2336 179-180 486.5 *** 2337 225-226 458.3 *** 2338 262-263 444.2 **2339   165-165.5 502.0 *** 2340 186-187 506.5 *** 2341 93-95 469.4 ***2342 163-165 498.6 *** 2343 174-175 490.5 ** 2344 98-99 482.6 *** 2345166-167 498.5 (M − 1) ** 2346 177-178 476.6 *** 2347 glass 476.6 ***2348 glass 440.5 ** 2349 183-184 476.3 * 2350 223-224 504.3 ** 2351180-181 500.3 (M − 1) *** 2352 255-256 520.0 * 2353 148-149 498.6 ***2354 217-219 483.7 *** 2355 205-207 490.5 ** 2356 200-201 472.4 (M− 1) * 2357 181-182 456.4 (M − 1) * 2358 194-196 458.3 (M − 1) * 2359234-236 486.5 ** 2360 177-179 488.5 *** 2361 243-245 454.7 *** 2362260-262 448.5 * 2363 225-227 462.7 ** 2364 250-251 476.6 *** 2365202-204 474.6 ** 2366 241-243 490.6 *** 2367 214-216 476.5 *** 2368178-182 460.6 ** 2369 189-191 474.6 ** 2370 177-179 502.6 *** 2371213-215 492.5 *** 2372 225-227 518.6 *** 2373 179-180 472.5 *** 2374113-115 446.5 *** 2375 227-229 488.8 *** ¹H NMR (300 MHz, CDCl₃): □8.58(d, 2H, J = 4.5 Hz), 7.79 (d, 1H, J = 8.7 Hz), 7.51 (d, 1H, J = 8.7 Hz),7.05-7.36 (m, 6H), 6.58 (s, 1H), 3.99 (d, 2H, J = 6.6 Hz), 3.20 (t, 2H,J = 7.8 Hz), 1.96 (m, 2H), 1.09 (t, 3H, J = 7.5 Hz), 1.04 (m, 1H), 0.56(m, 2H), 0.04 (m, 2H). 2376 181-183 494.6 *** 2377 166-168 488.6 ***2378 179-180 499.8 *** 2379 211-213 498.9 (M − 1) *** ¹H NMR (300 MHz,CDCl₃): □ 8.58 (d, 2H, J = 4.5 Hz), 7.79 (d, 1H, J = 8.4 Hz), 7.60 (d,1H, J = 1.5 Hz), 7.06-7.46 (m, 6H), 6.42 (s, 1H), 4.85 (m, 1H), 4.02 (t,1H, J = 8.1 Hz), 2.57-2.79 (m, 4H), 2.30-2.37 (m, 4H), 1.78-2.07 (m,4H). 2380 221-223 502.9 *** 2381 218-221 488.0 *** 2382 113-118 488.6*** 2383 114-122 503.3 *** 2384 183-185 472.6 ** 2385 211-213 470.4 **2386 194-196 472.7 * 2387 222-224 484.4 ** 2388 215-216 470.7 *** 2389201-202 472.7 * 2390 234-238 487.0 *** 2391 222-224 488.9 *** 2392106-109 456.4 *** 2393 143-144 512.8 *** 2394 203-204 488.2 ** 2395221-222 494.0 *** 2396 179-180 468.8 *** 2397 143-145 452.7 * 2398 glass466.7 ** 2399  94-104 468.7 *** 2400 193-196 442.7 *** 2401 107-110477.7 *** 2402 193-195 400.6 ** 2403 189-191 414.6 * 2404 168-170 450.9** 2405 173-175 456.9 * 2406 176-178 474.6 *** 2407 210-212 436.9 **2408 230-236 466.8 * 2409 168-174 438.7 ** 2410 143-144 462.7 ** 241191-92 492.7 ** 2412 144-145 472.7 *** 2413 92-93 497.9 *** 2414 91-93485.9 *** 2415 88-90 513.0 *** 2416 215-219 477.7 ** 2417 118-120 477.8*** 2418 235-237 478.8 *** 2419 212-214 478.6 *** 2420 237-241 436.7 **2421 211-215 450.8 ** 2422 157-165 452.8 *** 2423 218-220 488.7 ** 2424220-222 501.0 *** 2425 233-236 448.6 ** 2426 243-246 478.9 ** 2427150-154 451.0 ** 2428 216-222 477.1 ** 2429 189-192 472.7 *** 2430198-201 471.6 *** 2431 234-237 472.7 ** 2432 478.9 * 2433 glass 478.7*** 2434 215-217 410.1 *** ¹H NMR (300 MHz, CDCl₃): □0.67-0.76 (m, 2H),0.96-1.05 (m, 2H), 1.27 (d, 6H), 3.33-3.42 (m, 1H), 3.64-3.79 (m, 1H),3.82 (d, br, 1H), 6.68 (d, 2H), 7.05 (t, 1H), 7.10-7.13 (dd, 1H),7.45-7.53 (m, 3H), 7.72 (d, 1H), 8.458 (d, 2H) 2435 108-113 467.0 * 2436** ¹H NMR (300 MHz, CDCl₃): □7.78-7.74 (2H, m), 7.56 (2H, d, J = 6.9Hz), 7.44 (2H, d, J = 6.9 Hz), 7.33-7.29 (2H, m), 6.77 (1H, br s), 4.99(1H, 5, J = 9.3 Hz), 4.37-4.33 (1H, m), 2.89-2.82 (2H, m), 2.39-2.33(2H, m), 2.02-1.76 (2H, m), 1.39 (3H, d, J = 6.6 Hz), 1.12-0.98 (1H, m),0.62-0.44 (3H, m), 0.36-0.27 (1H, m) 2437 186-190 451.3 *** 2438 234-237485.3 *** 2439 209-211 501.3 *** 2440 152-154 450.1 *** 2441 434.8 ***2442 228-230 448.9 *** 2443 208-210 471.3 *** 2444 105-110 477.3 ***2445 94-95 487.9 *** 2446 82-83 501.8 *** 2447 89-90 481.8 *** 2448192-195 487.9 *** 2449 209-210 467.0 ** 2450 211-213 490.8 (M − 1) **2451 194-196 424.6 (M − 1) ** 2452 267-269 459.7 ** 2453 165-169 486.6*** 2454 182-185 501.8 *** 2455 72-84 511.0 *** 2456 176-178 485.0 ***2457 152-155 504.7 *** 2458 209-211 446.0 *** 2459 205-207 458.9 ***2460 200-202 469.9 *** 2461 230-232 472.1 *** 2462 218-219 471.4 ***2463 228-230 483.6 *** 2464 222-223 497.6 *** 2465 227-229 485.6 ***2466 144-145 499.9 *** 2467 89-90 442.8 *** 2468 153-154 441.6 *** 2469210-212 423.5 *** 2470 187-189 423.5 *** 2471 171-176 436.5 *** 2472191-194 436.4 *** 2473 87-88 469.4 *** 2474 91-92 443.4 *** 2475 90-91463.3 ** 2476 228-229 450.6 *** 2477 178-179 477.8 *** 2478 157-159451.8 *** 2479 102-103 527.8 *** 2480 221-222 474.1 *** 2481 193-194440.0 *** 2482 212-214 442.4 *** 2483 92-98 485.0 *** 2484 207-208 502.0*** 2485 222-224 383.1 *** 2486 239-241 469.0 *** 2487 199-201 528.9 ***2488 226-228 528.8 *** 2489 166-169 527.7 *** 2490 114-115 508.0 ***2491 177-178 516.0 *** 2492 215-216 502.0 * 2493 170-171 507.9 *** 2494466.0 *** 2495 159-160 477.6 (M − 1) *** 2496 195-196 465.8 *** 2497195-196 453.9 *** 2498 452.8 *** 2499 226-228 475.4 (M − 1) ** 2500524.4 *** 2501 516.0 * 2502 529.9 ** 2503 497.9 ** 2504 82-88 460.9 ***2505 203-204 410.1 *** 2506 214-215 487.6 *** 2507 222-223 501.9 ***2508 203-205 488.1 *** 2509 126-130 522.0 *** 2510 165-169 477.7 (M − 1)*** 2511 209-228 452.9 *** 2512 175-177 453.9 *** 2513 206-208 425.7 **2514 150-152 416.1 ** 2515 184-185 410.1 *** 2516 201-203 436.0 *** 2517190-191 469.9 [M − 1] *** 2518 140-142 486.0 (M − 1) *** 2519 204-207472.0 (M − 1) *** 2520 170-171 469.9 (M − 1) *** 2521 198-200 485.9 (M− 1) *** 2522 248-258 440.0 *** 2523 521.9 *** 2524 236-245 438.9 ***2525 169-195 466.0 *** 2526 196-197 467.9 *** 2527 151-152 471.8 ***2528 168-169 485.6 (M − 1) *** 2529 174-175 493.9 *** 2530 165-166 497.8*** 2531 173-174 511.8 (M − 1) *** 2532 67-68 442.1 *** 2533 94-95 468.8*** 2534 108-115 505.8 *** 2535 192-194 516.0 ** 2536 231-238 502.1 ***2537 190-201 486.1 *** 2538 229-237 499.9 *** 2539 216-218 517.9 ***2540 149-152 505.9 *** 2541  96-108 528.2 *** 2542 115-122 549.7 ***2543 115-124 550.6 *** 2544 148-150 483.5 (M − 1) *** 2545 87-89 485.5(M − 1) ***

Example 7 Evaluation of the Activity of Compounds Using anHCV-Poliovirus Chimera

In an HCV-poliovirus (HCV-PV) chimera, the PV 5′ UTR is replaced by theHCV 5′ UTR and partial (the first 123 amino acids) core coding sequences(nucleotides 18 to 710 of HCV 1b) as shown in FIG. 1 (139, 140). As aconsequence, the expression of poliovirus proteins is under regulationof the HCV IRES. Poliovirus is a picornavirus in which proteintranslation initiation is mediated by an IRES element located in the 5′UTR. At the 5′ end of the HCV-PV chimeric genome, there is thecloverleaf-like RNA structure of PV, an essential cis-acting replicationsignal ending with the genome-linked protein VPg. Replication kineticsof the HCV-PV chimera matches that of the parental poliovirus (Mahoney)and can result in cytopathic effects (CPE) in cell culture. Heptazyme(29), a ribozyme that targets the HCV IRES, was shown to be activeagainst the chimeric virus in cell culture (76, 77).

To evaluate compounds for activity against the chimeric virus, HeLacells are seeded and incubated at 37° C. under 5% CO₂ for 24 hours. Thecells are then infected with HCV-PV at a multiplicity of infection (MOI)at 0.1 for 30 min and then treated with compound for 1 day (treatmenttime will be optimized). The activity of compounds is determined by achange in cytopathic effect, plaque assay, and/or viral RNA production(see e.g., Table 1).

Example 8 Evaluation of the Activity of Compounds Against a Wild-TypePoliovirus (WT-PV) and the Poliovirus IRES Translation Assay (WT-PV monoluc)

A DNA construct is prepared, termed pPVIRESmono, in which PV IRESsequences are inserted (nuclotide number 1-742) between a promoter andthe firefly luciferase (Fluc) reporter gene. A stably transfected 293 Tcell line, is established by transfection with the pPVIRESmono DNA byselecting for resistance to hygromycin. As previously described, cellsare treated with compounds for 20 hours, and activity is determined byquantifying the Fluc signal. Additionally, to evaluate compoundsactivity against wild-type poliovirus, Helacells are seeded andincubated at 37° C. under 5% CO₂ for 24 hours. Cells are then infectedwith wild-type poliovirus at a MOI at 0.1 for 30 minutes, and thentreated with compound for one day. The activity of compounds isdetermined by changes in cytopathic effect, plaque assay, and RT-PCRusing poliovirus IRES primers and probes (see e.g., Table 2).

Furthermore, if compounds are active against the poliovirus and othervirus IRES, then the compounds are useful for treating viral infectionby any virus containing an IRES. TABLE 2 WTPV WT-PV CPE WT-PV CPE WT-PVCPE mono luc Compound No. (100 μM)* (10 μM)* (1 μM)* IC₅₀ (μM) 4 3 2 10.8 5 3 2 1 9 9 3 2 2 >100 10 3 2 2 >100 19 3 2 1 15 24 3 2 2 1.5

Example 9 In vitro Translation Assay

In vitro translation assays can be used to distinguish between thecompounds that act on HCV IRES RNA or cellular translation factors. Inexemplary assays, the mRNA that will direct translation is a transcribedrunoff product from the T7 RNA polymerase promoter of the pHCVIRESmonoplasmid DNA generated with Ambion RNA MegaTranscript kit (Ambion, Inc.,Austin, Tex.). In vitro translation is performed using HeLa cell lysatesusing methods known to one of skill in the art. Preliminary resultsindicate that one or more of the compounds of the present invention hassignificantly higher activity against HCV IRES regulated translationafter preincubating the compound with the HCV IRES RNA transcripts thanafter preincubating with HeLa cell lysate for 30 min at 37° C. orwithout preincubation (data not shown). This suggests that this compoundmay interact with the HCV IRES RNA in the in vitro translation assay. Todemonstrate whether the compounds selectively act on the HCV IRES, pLucis used together with cellular IRES mRNA transcripts as controls for invitro translation.

All publications and patent applications cited herein are incorporatedby reference to the same extent as if each individual publication orpatent application was specifically and individually indicated to beincorporated by reference.

Although certain embodiments have been described in detail above, thosehaving ordinary skill in the art will clearly understand that manymodifications are possible in the embodiments without departing from theteachings thereof. All such modifications are intended to be encompassedwithin the claims of the invention.

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All documents referred to herein are incorporated by reference into thepresent application as though fully set forth herein.

1. A compound of formula I

wherein: X is: a nitro group; a cyano group; a —COR_(a) group, whereR_(a) is: a C₁ to C₆ alkyl, a C₆ to C₈ aryl optionally substituted withan alkoxy or a halogen, or a dialkyl-amino; a —COOR_(x) group, whereR_(x) is a C₁ to C₆ alkyl; a formyl group; a C₆ to C₈ aryl optionallysubstituted with an alkoxy; or a 5 or 6-membered heteroaryl optionallysubstituted with: a C₁ to C₆ alkyl, a C₆ to C₈ aryl optionallysubstituted with an alkoxy or one or more halogen(s), or a 5 to 6membered heteroaryl; Y is: a haloalkyl; a halogen; a benzofuran; abenzothiophene; a dibenzofuran; a dibenzothiophene; a benzothiazole; anaphthalene; an indole, optionally substituted on the nitrogen with a C₁to C₆ alkyl;

where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as definedabove, or an —SO₂R_(x), where R_(x) is as defined above; or

where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl; a —NHCOR_(e) group,where R_(e) is: a C₁ to C₆ alkyl; a C₆ to C₈ aryl optionally substitutedwith: a C₁ to C₆ alkyl, an alkoxy, a cyano group, a nitro group, or ahalogen; a —NHCOOR_(x) group, where R_(x) is as defined above; a—CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl; a —NR_(g)R_(h) group,where R_(g) is hydrogen or a C₁ to C₆ alkyl and R_(h) is hydrogen or aC₆ to C₈ aryl optionally substituted with an alkoxy; a C_(l) to C₆alkyl; a 5 or 6 membered heteroaryl, optionally substituted with: a C₁to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl, a C₆ to C₈aryl, optionally substituted with —COOR_(x), where R_(x) is as definedabove, or an amino group; a 5 or 6 membered heterocycle optionallysubstituted with: a —COOR_(x) group, where R_(x) is as defined above, ora —NHCOOR_(x) group, where R_(x) is as defined above; a C₆ to C₈ aryl,optionally substituted with one or more of the following: an alkoxy,optionally substituted with: an alkoxy, a hydroxy, one or morehalogen(s), a 5 or 6 membered heterocycle, optionally substituted with:a C₁ to C₆ alkyl, or a hydroxy, an amino group optionally substitutedwith one or more C₁ to C₆ alkyl(s), a —NR_(i)SO₂R_(x) group, where R_(x)is as defined above and R_(i) is: a hydrogen, a C₁ to C₆ alkyl, a—COR_(x) group, where R_(x) is as defined above, a haloalkyl, or ahaloalkoxy, a —NR_(j)COR_(k) group, where R_(x) is: a C₁ to C₆ alkyl, ahydrogen, or an amino optionally substituted with one or more C₁ to C₆alkyl(s), and R_(j) is: a hydrogen, a C₁ to C₆ alkyl, a COR_(x) group,where R_(x) is as defined above, a haloalkyl, or a haloalkoxy, a N═N⁺═N⁻group, or a —COR₁, where R_(l) is a 5 or 6 membered heterocycleoptionally substituted with a hydroxy, an amino optionally substitutedwith one or more C₁ to C₆ alkyl(s), a C₁ to C₆ alkyl group, optionallysubstituted with: a —NHSO₂R_(x) group, where R_(x) is as defined above,or a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above, ahaloalkoxy, a halogen, a hydroxy, a —COOR_(x) group, where R_(x) is asdefined above, a COR_(m) group, where R_(m) is: an amino optionallysubstituted with one or more C₁ to C₆ alkyl(s), where the one or more C₁to C₆ alkyl(s) is/are optionally substituted with: a hydroxy a 5 or 6membered heterocycle, an amino optionally substituted with one or moreC₁ to C₆ alkyl(s), an alkoxy, a 3 to 7 membered heterocycle, optionallysubstituted with a C₁ to C₆ alkyl, optionally substituted with adialkyl-amino, a —NHR_(n) group, where R_(n) is: a —CH₂CONH₂, or a C₆ toC₈ aryl optionally substituted with: an alkyl, one or more halogen(s), anitro group, or one or more alkoxy(s), a —NR_(o)COR_(p) group, whereR_(p) is: a C₁ to C₆ alkyl optionally substituted with: a halogen, analkoxy, or a C₆ to C₈ aryl, a 5 or 6 membered heterocycle, a C₆ to C₈aryl, optionally substituted with a halogen, a 5 or 6 memberedheteroaryl optionally substituted with one or more C₁ to C₆ alkyl(s), ahydrogen,

and where R_(o) is: a hydrogen, a C₁ to C₆ alkyl, a —COR_(x) group,where R_(x) is as defined above, a haloalkyl, or a haloalkoxy, a—NR_(q)CONR_(q)R_(r) group, where R_(q) is: a hydrogen, a C₁ to C₆alkyl, a haloalkyl, a haloalkoxy, or a —COR_(x) group, where R_(x) is asdefined above, and where R_(r) is: a C₆ to C₈ aryl optionallysubstituted with:

a C₁ to C₆ alkyl, a haloalkyl, a —OR_(s) group, where R_(s) is a C₆ toC₈ aryl, or a —COOR_(x) group, where R_(x) is as defined above, a C₁ toC₆ alkyl optionally substituted with one or more of the following: ahalogen, an alkylene, a C₆ to C₈ aryl, and/or a —COOR_(x) group, whereR_(x) is as defined above, a —COOR_(x) group, where R_(x) is as definedabove, a —NR_(t)COOR_(u) group, where R_(u) is: a C₁ to C₁₂ alkyl,optionally substituted with: a C₆ to C₈ aryl optionally substituted witha C₁ to C₆ alkyl or an alkoxy, an alkylene, an alkoxy, an alkyne, ahalogen, or a 5 or 6 membered heterocycle, a C₆ to C₈ aryl, optionallysubstituted with: an alkoxy, a halogen, or a C₁ to C₆ alkyl, or a 5 or 6membered heterocycle, and R_(t) is: a hydrogen, a C₁ to C₆ alkyl, a—COR_(x) group, where R_(x) is as defined above, a haloalkyl, or ahaloalkoxy, a —NR_(v)SO₂R_(w) group, where R_(v) is: a hydrogen, a—COR_(x), where R_(x) is as defined above, or a C₁ to C₆ alkyl,optionally substituted with: a halogen, a —COR_(x) group, where R_(x) isas defined above, a —OCOR_(x) group, where R_(x) is as defined above, ahydroxy, or an alkoxy, and where R_(w) is: a C₁ to C₆ alkyl optionallysubstituted with: a halogen, a haloalkyl, a C₆ to C₈ aryl, or a 5 or 6membered heterocycle, a C₂ to C₆ alkylene, an alkyl- or dialkyl-aminooptionally substituted with a halogen, a 5 or 6 membered heterocycle, ora 5 or 6 membered heteroaryl optionally substituted with: a C₁ to C₆alkyl, a 5 or 6 membered heterocycle, or

optionally substituted with a C₁ to C₆ alkyl, where R_(y) is a C₁ to C₆alkyl or hydrogen,

where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally substituted witha C₆ to C₈ aryl, a —SR_(x) group, where R_(x) is as defined above, a—SO₂R_(aa) group, where R_(aa) is: a C₁ to C₆ alkyl, an amino group, analkyl- or dialkyl-amino group optionally substituted with a hydroxy or a—COOR_(x) group, where R_(x) is as defined above, a 5 or 6 memberedheteroaryl, a C₆ to C₈ aryl, and/or a —NHR_(bb) group, where R_(bb) is:

a —C(═S)NH₂ group, or a —PO(OR_(x))₂ group, where R_(x) is as definedabove;

group, where R_(cc) is: a naphthalene, a 5 or 6 membered heteroaryl,

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing: an alkoxy, a hydroxy, a halogen, a C₁ to C₆ alkyl, optionallysubstituted with a cyano group, an amino optionally substituted with oneor more C₁ to C₆ alkyl(s), a —NHPOR_(x)R_(x), where R_(x) is as definedabove, a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen or aC₁ to C₆ alkyl, optionally substituted with a halogen, and R_(ff) is: ahydrogen, a haloalkyl, a haloalkoxy, a C₁ to C₆ alkyl, or a —COR_(x),where R_(x) is as defined above, a —NR_(gg)COR_(hh) group, where R_(hh)is: a hydrogen, a C₁ to C₆ alkyl optionally substituted with: an alkoxy,a halogen, or an amino optionally substituted with one or more C₁ to C₆alkyl(s), an amino optionally substituted with one or more C₁ to C₆alkyl(s), where the one or more C₁ to C₆ alkyl(s) is/are optionallysubstituted with a halogen, a 5 or 6 membered heterocycle, a 5 or 6membered heteroaryl, and R_(gg) is: a hydrogen, a C₁ to C₆ alkyl, ahaloalkyl, a haloalkoxy, or a —COR_(x) group, where R_(x) is as definedabove, a haloalkyl, 5 or 6 membered heterocycle groups, an aminooptionally substituted with one or more C₁ to C₆ alkyl(s), and/or a—NR_(ii)SO₂R_(x) group, where R_(x) is as defined above, and R_(ii) is:a hydrogen, a C₁ to C₆ alkyl, a haloalkyl, a haloalkoxy, a —COR_(x)group, where R_(x) is as defined above; Z is: a C₁ to C₆ alkyloptionally substituted with: an alkoxy, one or more halogen(s), or a C₆to C₈ aryl; a C₂ to C₆ alkylene; a C₆ to C₈ aryl optionally substitutedwith an alkoxy or one or more C₁ to C₆ alkyl(s); a —COOR_(x) group,where R_(x) is as defined above; or

R is a hydrogen, a halogen or an alkoxy; R₁ is: a hydrogen; a hydroxy; ahalogen; a haloalkyl; a nitro group; a 5 or 6 membered heteroaryl; a 5or 6 membered heterocycle; an alkoxy optionally substituted with: one ormore halogen(s), a C₆ to C₈ aryl, or a 5 or 6 membered heterocycle; a C₆to C₈ aryl optionally substituted with an alkoxy; a —COR_(x) group,where R_(x) is as defined above; a C₁ to C₆ alkyl optionally substitutedwith a dialkyl-amino or a 5 or 6 membered heterocycle; or R₁ joinstogether with R₂ to form:

R₂ is: a nitro group; a hydrogen; a halogen; a hydroxy group; a C₁ to C₆alkyl group, optionally substituted with one or more halogen(s); anamino group; an alkoxy group optionally substituted with: one or morehalogen(s), an —OCOR_(x) group, where R_(x) is as defined above, adialkyl-amino optionally substituted with an alkoxy, a 5 or 6 memberedheterocycle group optionally substituted with a C₁ to C₆ alkyl, a 5 or 6membered heteroaryl group, or a C₆ to C₈ aryl group; a —COOR_(x) group,where R_(x) is as defined above; a haloalkyl; an amide group optionallysubstituted with: a hydroxy group, or a C₆ to C₈ aryl; a 5 or 6 memberedheteroaryl; a —OCOR_(x) group, where R_(x) is as defined above; a—NHCOR_(jj) group, where R_(jj) is: an alkoxy, or an amino optionallysubstituted with one or more C₁ to C₆ alkyl(s); a —OR_(kk) group, whereR_(kk) is a 5 to 6 membered heteroaryl; a —NHSO₂R_(x) group, where R_(x)is as defined above; or R₂ joins together with R₁ to form:

R₃ is: a hydrogen; or CH₂OCOR_(x), and R_(x) is as defined above;provided that when X is phenyl substituted with alkoxy, Y is phenyl, Ris hydrogen, R₁ is a halogen, R₂ is hydrogen, and R₃ is hydrogen, andprovided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, Ris hydrogen, R₁ is hydrogen or hydroxy, R₂ is hydrogen or hydroxy, andR₃ is hydrogen, then Z is: a C₁ to C₆ alkyl substituted with: an alkoxy,one or more halogen(s), or a C₆ to C₈ aryl; a C₂ to C₆ alkylene; a C₆ toC₈ aryl optionally substituted with an alkoxy or one or more C₁ to C₆alkyl(s); a —COOR_(x) group, where R_(x) is as defined above; or

or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, wherein X is a nitro group or a cyano group.
 3. The compound of claim1, wherein X is a cyano group.
 4. The compound of claim 1, wherein: Y isa C₆ to C₈ aryl, optionally substituted with one or more of thefollowing: an amino optionally substituted with one or more C₁ to C₆alkyl(s), a C₁ to C₆ alkyl group, optionally substituted with a—NHSO₂R_(x) group, a —NR_(o)COR_(p) group, where R_(p) is: a C₁ to C₆alkyl optionally substituted with: a halogen, or a C₆ to C₈ aryl, or a 5or 6 membered heterocycle, and where R_(o) is a hydrogen, a—NR_(q)CONR_(q)R_(r) group, where R_(q) is: a hydrogen, or a C₁ to C₆alkyl, and where R_(r) is a C₁ to C₆ alkyl optionally substituted withone or more of the following: a halogen, an alkylene, or a C₆ to C₈aryl, a —NR_(t)COOR_(u) group, where R_(u) is: a C₁ to C₁₂ alkyl,optionally substituted with: a C₆ to C₈ aryl optionally substituted witha C₁ to C₆ alkyl or an alkoxy, an alkylene, an alkoxy, an alkyne, ahalogen, or a 5 or 6 membered heterocycle, a C₆ to C₈ aryl, optionallysubstituted with an alkoxy, a 5 or 6 membered heterocycle, and whereR_(t) is: a hydrogen, or a C₁ to C₆ alkyl, a —NR_(v)SO₂R_(w) group,where R_(v) is a hydrogen, and where R_(w) is a C₁ to C₆ alkyloptionally substituted with a halogen;

where R_(z) is a C₁ to C₆ alkyl, and/or a —NHR_(bb) group, where R_(bb)is a —PO(OR_(x))₂ group.
 5. The compound of claim 4, wherein Y is a C₆to C₈ aryl substituted with: a —NR_(q)CONR_(q)R_(r) group, a—NR_(t)COOR_(u) group, a —NR_(v)SO₂R_(w) group, or a —NHR_(bb) group,where R_(bb) is -a —PO(OR_(x))₂ group.
 6. The compound of claim 5,wherein the C₆ to C₈ aryl is phenyl.
 7. The compound of claim 6, whereinthe phenyl is substituted at the para position.
 8. The compound of claim7, wherein Y is phenyl substituted with a —NR_(q)CONR_(q)R_(r) group atthe para position.
 9. The compound of claim 7, wherein Y is phenylsubstituted with a —NR_(t)COOR_(u) group at the para position.
 10. Thecompound of claim 7, wherein Y is phenyl substituted with a—NR_(v)SO₂R_(w) group at the para position.
 11. The compound of claim 7,wherein Y is phenyl substituted with a —NHPO(OR_(x))₂ group at the paraposition.
 12. The compound of claim 1, wherein Z is: a C₁ to C₆ alkyloptionally substituted with an alkoxy, or one or more halogen(s), or aC₂ to C₆ alkylene.
 13. The compound of claim 1, wherein Z is a C₁ to C₆alkyl.
 14. The compound of claim 13, wherein Z is a -a C₂ to C₅ alkyl.15. The compound of claim 14, wherein Z is cyclobutyl, cyclopropyl,cyclopropylmethyl, ethyl or cyclopentyl.
 16. The compound of claim 1,wherein R is hydrogen.
 17. The compound of claim 1, wherein R₁ is: ahydrogen; an alkoxy group optionally substituted with: one or morehalogen(s), a C₆ to C₈ aryl group, or a 5 or 6 membered heterocycle; orR₁ joins together with R₂ to form:


18. The compound of claim 1, wherein R₂ is: a hydrogen; a halogen; ahydroxy group; a C₁ to C₆ alkyl group, optionally substituted with oneor more halogen(s); an amino group; an alkoxy group optionallysubstituted with: one or more halogen(s), an —OCOR_(x) group, whereR_(x) is as defined above, a dialkyl-amino optionally substituted withan alkoxy, a 5 or 6 membered heterocycle group optionally substitutedwith a C₁ to C₆ alkyl, a 5 or 6 membered heteroaryl group, or a C₆ to C₈aryl group; a —COOR_(x) group; or R₂ joins together with R₁ to form:


19. The compound of claim 1, wherein: at least one of R₁ and R₂ is ahydroxy group or an alkoxy group optionally substituted with: one ormore halogen(s), a C₆ to C₈ aryl group, or a 5 or 6 membered heterocyclegroup; or R₂ is a —OCOR_(x) group, a —OR_(kk) group, or an alkoxy groupsubstituted with: an —OCOR_(x) group, a dialkyl-amino optionallysubstituted with an alkoxy, a 5 or 6 membered heterocycle groupsubstituted with a C₁ to C₆ alkyl; or a 5 or 6 membered heteroarylgroup.
 20. The compound of claim 19, wherein R₂ is an alkoxy groupoptionally substituted with: a 5 or 6 membered heterocycle groupoptionally substituted with a C₁ to C₆ alkyl; or a 5 or 6 memberedheteroaryl group.
 21. The compound of claim 20, wherein R₂ is a C₁ to C₆alkoxy group optionally substituted with: a 5 or 6 membered heterocyclegroup optionally substituted with a C₁ to C₆ alkyl; or a 5 or 6 memberedheteroaryl group.
 22. The compound of claim 1, wherein R₃ is a hydrogen.23. The compound of claim 1, wherein: X is a cyano group; Y is a C₆ toC₈ aryl substituted with: a —NR_(q)CONR_(q)R_(r) group, a—NR_(t)COOR_(u) group, a —NR_(v)SO₂R_(w) group, or a —NHPO(OR_(x))₂group; Z is: a C₁ to C₆ alkyl optionally substituted with an alkoxy, orone or more halogen(s), or a C₂ to C₆ alkylene; R is hydrogen; at leastone of R₁ and R₂ is a hydroxy group or an alkoxy group optionallysubstituted with: one or more halogen(s), a C₆ to C₈ aryl group, or a 5or 6 membered heterocycle group; or R₂ is a —OCOR_(x) group, a —OR_(kk)group, or an alkoxy group substituted with: an —OCOR_(x) group, adialkyl-amino optionally substituted with an alkoxy, a 5 or 6 memberedheterocycle group substituted with a C₁ to C₆ alkyl; or a 5 or 6membered heteroaryl group; and R₃ is hydrogen.
 24. The compound of claim23, wherein Y is a phenyl substituted with a —NR_(q)CONR_(q)R_(r) group.25. The compound of claim 24, wherein: Z is a C₁ to C₆ alkyl; and R₂ isan alkoxy group optionally substituted with: a 5 or 6 memberedheterocycle group optionally substituted with a C₁ to C₆ alkyl; or a 5or 6 membered heteroaryl group.
 26. The compound of claim 23, wherein Yis a phenyl substituted with a —NR_(t)COOR_(u) group.
 27. The compoundof claim 26, wherein: Z is a C₁ to C₆ alkyl; and R₂ is an alkoxy groupoptionally substituted with: a 5 or 6 membered heterocycle groupoptionally substituted with a C₁ to C₆ alkyl; or a 5 or 6 memberedheteroaryl group.
 28. The compound of claim 23, wherein Y is a phenylsubstituted with a —NR_(v)SO₂R_(w) group.
 29. The compound of claim 28,wherein: Z is a C₁ to C₆ alkyl; and R₂ is an alkoxy group optionallysubstituted with: a 5 or 6 membered heterocycle group optionallysubstituted with a C₁ to C₆ alkyl; or a 5 or 6 membered heteroarylgroup.
 30. The compound of claim 23, wherein Y is -a —NHPO(OR_(x))₂group.
 31. The compound of claim 30, wherein: Z is a C₁ to C₆ alkyl; andR₂ is an alkoxy group optionally substituted with: a 5 or 6 memberedheterocycle group optionally substituted with a C₁ to C₆ alkyl; or a 5or 6 membered heteroaryl group.
 32. The compound of claim 1, wherein: Xis: a cyano group; or a formyl group; Y is: a 5 or 6 memberedheteroaryl, optionally substituted with a C₆ to C₈ aryl, optionallysubstituted with —COOR_(x), where R_(x) is as defined above; or a C₆ toC₈ aryl, optionally substituted with one or more of the following: a C₁to C₆ alkyl group; an amino optionally substituted with one or more C₁to C₆ alkyl(s); a halogen; a hydroxy; a —COR_(m) group, where R_(m) isan amino optionally substituted with one or more C₁ to C₆ alkyl(s); a—NR_(o)COR_(p) group, where R_(p) is a C₁ to C₆ alkyl optionallysubstituted with an alkoxy, and where R_(o) is a hydrogen; a—NR_(q)CONR_(q)R_(r) group, where R_(q) is hydrogen and where R_(r) is aC₁ to C₆ alkyl; a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, andwhere R_(u) is a C₁ to C₁₂ alkyl, optionally substituted with: a C₆ toC₈ aryl; a halogen; or a 5 or 6 membered heterocycle; a —NR_(v)SO₂R_(w)group, where R_(v) is hydrogen and where R_(w) is a C₁ to C₆ alkyl; oran alkyl- or dialkyl-amino;

where R_(z) is hydrogen or a C₁ to C₆ alkyl; a —SO₂R_(aa) group, whereR_(aa) is: an amino group; or an alkyl or dialkyl amino group; or a—NHR_(bb) group, where R_(bb) is a —PO(OR_(x))₂ group, where R_(x) is asdefined above; Z is: a C₁ to C₆ alky; or a —COOR_(x) group, where R_(x)is as defined above; R is a hydrogen, R₁ is: a hydrogen; a 5 or 6membered heterocycle; or an alkoxy optionally substituted with: one ormore halogen(s); or a 5 or 6 membered heterocycle; R₂ is: a hydrogen; ahydroxy group; a C₁ to C₆ alkyl group, optionally substituted with oneor more halogen(s); an alkoxy group optionally substituted with: one ormore halogen(s); a 5 or 6 membered heterocycle group optionallysubstituted with a C₁ to C₆ alkyl; or a 5 or 6 membered heteroarylgroup; a —COOR_(x) group, where R_(x) is as defined above; an amidegroup; a 5 or 6 membered heteroaryl; or a —OR_(kk) group, where R_(kk)is a 5 to 6 membered heteroaryl; and R₃ is a hydrogen.
 33. The compoundof claim 32, wherein: X is a cyano group; Y is a C₆ to C₈ arylsubstituted with one or more of the following: an amino optionallysubstituted with one or more C₁ to C₆ alkyl(s); a —NR_(q)CONR_(q)R_(r)group, where R_(q) is hydrogen and where R_(r) is a C₁ to C₆ alkyl; a—NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where R_(u) is a C₁to C₁₂ alkyl, optionally substituted with a C₆ to C₈ aryl; or a—NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w) is a C₁to C₆ alkyl; Z is a C₁ to C₆ alky; R is a hydrogen, R₁ is a hydrogen; R₂is an alkoxy group optionally substituted with: one or more halogen(s);a 5 or 6 membered heterocycle group optionally substituted with a C₁ toC₆ alkyl; or a 5 or 6 membered heteroaryl group; or R₃ is a hydrogen.34. The compound of claim 32, wherein: X is a cyano group; Y is a C₆ toC₈ aryl substituted with one or more of the following: a C₁ to C₆ alkylgroup; an amino optionally substituted with one or more C₁ to C₆alkyl(s); a halogen; a —NR_(t)COOR_(u) group, where R_(t) is hydrogen,and where R_(u) is: a C₁ to C₁₂ alkyl; a —NR_(v)SO₂R_(w) group, whereR_(v) is hydrogen and where R_(w) is: a C₁ to C₆ alkyl; or an alkyl- ordialkyl-amino; Z is a C₁ to C₆ alky; R is a hydrogen; R₁ is a hydrogen;R₂ is a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;and R₃ is a hydrogen.
 35. The compound of claim 32, wherein: X is acyano group; Y is a C₆ to C₈ aryl substituted with one or more of thefollowing: a C₁ to C₆ alkyl; a halogen; a —NR_(t)COOR_(u) group, whereR_(t) is hydrogen, and where R_(u) is a C₁ to C₁₂ alkyl; a—NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w) is: a C₁to C₆ alkyl; or an alkyl- or dialkyl-amino; or a —NE_(q)CONR_(q)R_(r)group, where R_(q) is hydrogen and where R_(r) is a C₁ to C₆ alkyl; Z isa C₁ to C₆ alkyl; R is a hydrogen, R₁ is a hydrogen; R₂ is: an alkoxygroup optionally substituted with one or more halogen(s); an amide; a—OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl; or a 5 or6 membered heteroaryl; and R₃ is a hydrogen.
 36. The compound of claim35, wherein: X is a cyano group; Y is a C₆ to C₈ aryl substituted withone or more of the following: a halogen; a —NR_(t)COOR_(u) group, whereR_(t) is hydrogen, and where R_(u) is a C₁ to C₁₂ alkyl; or a—NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w) is a C₁to C₆ alkyl; Z is a C₁ to C₆ alkyl; R is a hydrogen; R₁ is a hydrogen;R₂ is a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;and R₃ is a hydrogen.
 37. The compound of claim 36, wherein the C₆ to C₈aryl is phenyl.
 38. The compound of claim 37, wherein the phenyl issubstituted at the para position.
 39. The compound of claim 38, whereinY is a phenyl substituted with a —NR_(t)COOR_(u) group, where R_(t) ishydrogen, and where R_(u) is a C₁ to C₁₂ alkyl.
 40. The compound ofclaim 38, wherein Y is a phenyl substituted with a halogen and a—NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where R_(u) is C₁ toC₁₂ alkyl.
 41. The compound of claim 38, wherein Y is a phenylsubstituted with a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogen andwhere R_(w) is C₁ to C₆ alkyl.
 42. The compound of claim 38, wherein Yis a phenyl substituted with a C₁ to C₆ alkyl and a —NR_(t)COOR_(u)group, where R_(t) is hydrogen, and where R_(u) is a C₁ to C₁₂ alkyl.43. The compound of claim 35, wherein: X is a cyano group; Y is a C₆ toC₈ aryl substituted with —NR_(t)COOR_(u) group, where R_(t) is hydrogen,and where R_(u) is a C₁ to C₁₂ alkyl; Z is a C₁ to C₆ alkyl; R is ahydrogen; R₁ is a hydrogen; R₂ is an alkoxy group optionally substitutedwith one or more halogen(s); and R₃ is a hydrogen.
 44. The compound ofclaim 35, wherein R₂ is an alkoxy group substituted with one or morehalogens.
 45. The compound of claim 43, wherein the C₆ to C₈ aryl isphenyl.
 46. The compound of claim 45, wherein the phenyl is substitutedat the para position.
 47. The compound of claim 35, wherein: X is acyano group; Y is a C₆ to C₈ aryl substituted with one or more of thefollowing: a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and whereR_(u) is a C₁ to C₁₂ alkyl; or a —NR_(q)CONR_(q)R_(r) group, where R_(q)is hydrogen and where R_(r) is a C₁ to C₆ alkyl; Z is a C₁ to C₆ alkyl;R is a hydrogen, R₁ is a hydrogen; R₂ is a 5 or 6 membered heteroaryl;and R₃ is a hydrogen.
 48. The compound of claim 47, wherein the C₆ to C₈aryl is phenyl.
 49. The compound of claim 48, wherein the phenyl issubstituted at the para position.
 50. The compound of claim 49, whereinY is a phenyl substituted with a —NR_(t)COOR_(u) group, where R_(t) ishydrogen, and where R_(u) is a C₁ to C₁₂ alkyl.
 51. The compound ofclaim 49, wherein Y is a C₆ to C₈ aryl substituted with aNR_(q)CONR_(q)R_(r) group, where R_(q) is hydrogen and where R_(r) is aC₁ to C₆ alkyl.
 52. The compound of claim 35, wherein: X is a cyanogroup; Y is a C₆ to C₈ aryl substituted with a —NR_(t)COOR_(u) group,where R_(t) is hydrogen, and where R_(u) is a C₁ to C₁₂ alkyl; Z is a C₁to C₆ alkyl; R is a hydrogen; R₁ is a hydrogen; R₂ is an amide; and R₃is a hydrogen.
 53. The compound of claim 52, wherein the C₆ to C₈ arylis phenyl.
 54. The compound of claim 53, wherein the phenyl issubstituted at the para position.
 55. The compound of claim 35, whereinR₂ is an alkoxy group substituted with one or more halogen(s).
 56. Thecompound of claim 35, wherein R₂ is a —OR_(kk) group, where R_(kk) is a5 to 6 membered heteroaryl.
 57. The compound of claim 32, wherein: X isa formyl group; Y is a C₆ to C₈ aryl substituted with one or more of thefollowing: a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and whereR_(u) is a C₁ to C₁₂ alkyl; or a —NR_(q)CONR_(q)R_(r) group, where R_(q)is hydrogen and where R_(r) is a C₁ to C₆ alkyl; Z is a C₁ to C₆ alkyl;R is a hydrogen; R₁ is a hydrogen; R₂ is an alkoxy group; and R₃ is ahydrogen.
 58. The compound of claim 32, wherein: X is a cyano group; Yis a C₆ to C₈ aryl substituted with one or more of the following: a C₁to C₆ alkyl group; a halogen; a —NR_(t)COOR_(u) group, where R_(t) ishydrogen, and where R_(u) is a C₁ to C₁₂ alkyl, optionally substitutedwith a C₆ to C₈ aryl; a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogenand where R_(w) is: a C₁ to C₆ alkyl; or an alkyl- or dialkyl-amino; or

Z is a C₁ to C₆ alkyl; R is a hydrogen; R₁ is a hydrogen; R₂ is analkoxy group substituted with one or more halogen(s); and R₃ is ahydrogen.
 59. The compound of claim 32, wherein: X is a cyano group; Yis a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing: a —NR_(o)COR_(p) group, where R_(p) is a C₁ to C₆ alkyloptionally substituted with an alkoxy, and where R_(o) is a hydrogen; Zis a C₁ to C₆ alkyl; R is a hydrogen; R₁ is a hydrogen; R₂ is an alkoxygroup substituted with a 5 or 6 membered heteroaryl group; and R₃ is ahydrogen.
 60. The compound of claim 32, wherein: X is a cyano group; Yis a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing: a C₁ to C₆ alkyl group; an amino optionally substituted withone or more C₁ to C₆ alkyl(s); a halogen; a —NR_(o)COR_(p) group, whereR_(p) is a C₁ to C₆ alkyl, and where R_(o) is a hydrogen; a—NR_(q)CONR_(q)R_(r) group, where R_(q) is hydrogen, and where R_(r) isa C₁ to C₆ alkyl; a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, andwhere R_(u) is a C₁ to C₁₂ alkyl; a —NR_(v)SO₂R_(w) group, where R_(v)is hydrogen, and where R_(w) is a C₁ to C₆ alkyl; or a —NHR_(bb) group,where R_(bb) is a —PO(OR_(x))₂ group, and where R_(x) is as definedabove; Z is a C₁ to C₆ alkyl; R is a hydrogen, R₁ is a hydrogen; R₂ is a5 or 6 membered heteroaryl; and R₃ is a hydrogen.
 61. The compound ofclaim 32, wherein: X is a cyano group; Y is a C₆ to C₈ aryl, optionallysubstituted with one or more of the following: an amino optionallysubstituted with one or more C₁ to C₆ alkyl(s); a —NR_(q)CONR_(q)R_(r)group, where R_(q) is hydrogen and where R_(r) is a C₁ to C₆ alkyl; a—NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where R_(u) is a C₁to C₁₂ alkyl, optionally substituted with: a C₆ to C₈ aryl; or a 5 or 6membered heterocycle; a —NR_(v)SO₂R_(w) group, where R_(v) is hydrogenand where R_(w) is a C₁ to C₆ alkyl;

where R_(z) is hydrogen or a C₁ to C₆ alkyl; Z is a C₁ to C₆ alkyl; R isa hydrogen, R₁ is: a 5 or 6 membered heterocycle; or an alkoxysubstituted with: one or more halogen(s); or a 5 or 6 memberedheterocycle; R₂ is a hydrogen; and R₃ is a hydrogen.
 62. The compound ofclaim 61, wherein R₁ is a 5 or 6 membered heterocycle.
 63. The compoundof claim 61, wherein R₁ is an alkoxy substituted with one or morehalogen.
 64. The compound of claim 61, wherein: Y is a C₆ to C₈ arylsubstituted with a —NR_(t)COOR_(u) group, where R_(t) is hydrogen, andwhere R_(u) is a C₁ to C₁₂ alkyl, optionally substituted with: a C₆ toC₈ aryl; or a 5 or 6 membered heterocycle; and R₁ is an alkoxysubstituted with one or more halogen.
 65. A compound of formula IIIa

wherein: X is hydrogen; Y is a C₆ to C₈ aryl, optionally substitutedwith one or more of the following: a —NR_(q)CONR_(q)R_(r) group, whereR_(q) is hydrogen and where R_(r) is a C₁ to C₆ alkyl; a —NR_(t)COOR_(u)group, where R_(t) is hydrogen, and where R_(u) is a C₁ to C₁₂ alkyl; ora —NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w) is a C₁to C₆ alkyl; Z is a C₁ to C₆ alkyl; R is a hydrogen, R₁ is a hydrogen;R₂ is: an alkoxy group optionally substituted with one or morehalogen(s); or a —OR_(kk) group, where R_(kk) is a 5 to 6 memberedheteroaryl; and R₃ is a hydrogen.
 66. The compound of claim 65, wherein:X is hydrogen; Y is a C₆ to C₈ aryl substituted with a —NR_(t)COOR_(u)group, where R_(t) is hydrogen, and where R_(u) is a C₁ to C₁₂ alkyl; Zis a C₁ to C₆ alkyl; R is a hydrogen; R₁ is a hydrogen; R₂ is a —OR_(kk)group, where R_(kk) is a 5 to 6 membered heteroaryl; and R₃ is ahydrogen.
 67. The compound of claim 65, wherein the C₆ to C₈ aryl isphenyl.
 68. The compound of claim 65, wherein the phenyl is substitutedat the para position.
 69. A pharmaceutical composition comprising: (i) acompound of formula I

wherein: X is: a nitro group; a cyano group; a —COR_(a) group, whereR_(a) is: a C₁ to C₆ alkyl; a C₆ to C₈ aryl optionally substituted withan alkoxy or a halogen; or a dialkyl-amino; a —COOR_(x) group, whereR_(x) is a C₁ to C₆ alkyl; a formyl group; a C₆ to C₈ aryl optionallysubstituted with an alkoxy; or a 5 or 6-membered heteroaryl optionallysubstituted with: a C₁ to C₆ alkyl; a C₆ to C₈ aryl optionallysubstituted with an alkoxy or one or more halogen(s); or a 5 to 6membered heteroaryl; Y is: a haloalkyl; a halogen; an amino optionallysubstituted with one or more C₁ to C₆ alkyl(s); a benzofuran; abenzothiophene; a dibenzofuran; a dibenzothiophene; a benzothiazole; anaphthalene; -an indole, optionally substituted on the nitrogen with aC₁ to C₆ alkyl;

where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as definedabove, or an —SO₂R_(x), where R_(x) is as defined above;

where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl; a —NHCOR_(e) group,where R_(e) is: a C₁ to C₆ alkyl; or a C₆ to C₈ aryl optionallysubstituted with: a C₁ to C₆ alkyl; an alkoxy; a cyano group; a nitrogroup; or a halogen; a —NHCOOR_(x) group, where R_(x) is as definedabove; a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl; a—NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a hydrogen andR_(h) is a C₆ to C₈ aryl optionally substituted with an alkoxy; a C₁ toC₆ alkyl; a 5 or 6 membered heteroaryl, optionally substituted with: aC₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl; a C₆ to C₈aryl, optionally substituted with —COOR_(x), where R_(x) is as definedabove; or an amino group; a 5 or 6 membered heterocycle optionallysubstituted with: a —COOR_(x) group, where R_(x) is as defined above; ora —NHCOOR_(x) group, where R_(x) is as defined above; a C₆ to C₈ aryl,optionally substituted with one or more of the following: an alkoxy,optionally substituted with: an alkoxy; a hydroxy; one or morehalogen(s); a 5 or 6 membered heterocycle, optionally substituted with:a C₁ to C₆ alkyl; or a hydroxy; an amino group optionally substitutedwith one or more C₁ to C₆ alkyl(s); a —NR_(i)SO₂R_(x) group, where R_(x)is as defined above, and where R_(i) is: a hydrogen; a C₁ to C₆ alkyl; a—COR_(x) group, where R_(x) is as defined above; a haloalkyl; or ahaloalkoxy; a —NR_(j)COR_(k) group, where R_(k) is: a C₁ to C₆ alkyl; ahydrogen; or an amino optionally substituted with one or more C₁ to C₆alkyl(s); and where R_(j) is: a hydrogen; a C₁ to C₆ alkyl; a —COR_(x)group, where R_(x) is as defined above; a haloalkyl; or a haloalkoxy; a—N═N⁺═N⁻ group; or a —COR₁, where R₁ is a 5 or 6 membered heterocycleoptionally substituted with a hydroxy; an amino optionally substitutedwith one or more C₁ to C₆ alkyl(s); a nitro group; a C₁ to C₆ alkylgroup, optionally substituted with: a —NHSO₂R_(x) group, where R_(x) isas defined above; or a —NR_(x)SO₂R_(x) group, where R_(x) is as definedabove; a haloalkoxy; a halogen; a hydroxy; a —COOR_(x) group, whereR_(x) is as defined above; a —COR_(m) group, where R_(m) is: an aminooptionally substituted with one or more C₁ to C₆ alkyl(s), where the C₁to C₆ alkyls are optionally substituted with: a hydroxy; a 5 or 6membered heterocycle; an amino optionally substituted with one or moreC₁ to C₆ alkyl(s); or an alkoxy; a 3 to 7 membered heterocycle,optionally substituted with a C₁ to C₆ alkyl, optionally substitutedwith a dialkyl-amino; a —NHR_(n) group, where R_(n) is: a —CH₂CONH₂; ora C₆ to C₈ aryl optionally substituted with: an alkyl; one or morehalogen(s); a nitro group; or one or more alkoxy(s); a —NR_(o)COR_(p)group, where R_(p) is: a C₁ to C₆ alkyl optionally substituted with: ahalogen; an alkoxy; or a C₆ to C₈ aryl; a 5 or 6 membered heterocycle; aC₆ to C₈ aryl, optionally substituted with a halogen; a 5 or 6 memberedheteroaryl optionally substituted with one or more C₁ to C₆ alkyl(s); ahydrogen;

and where R_(o) is: a hydrogen; a C₁ to C₆ alkyl; a —COR_(x) group,where R_(x) is as defined above; a haloalkyl; or a haloalkoxy; a—NR_(q)CONR_(q)R_(r) group, where R_(q) is: a hydrogen; a C₁ to C₆alkyl; a haloalkyl; a haloalkoxy; or a —COR_(x) group, where R_(x) is asdefined above, and where R_(r) is: a C₆ to C₈ aryl optionallysubstituted with:

a C₁ to C₆ alkyl; a haloalkyl; a —OR_(s) group, where R_(s) is a C₆ toC₈ aryl; or a —COOR_(x) group, where R_(x) is as defined above; a C₁ toC₆ alkyl optionally substituted with one or more of the following: ahalogen; an alkylene; a C₆ to C₈ aryl; and/or a —COOR_(x) group, whereR_(x) is as defined above; or a —COOR_(x) group, where R_(x) is asdefined above; a —NR_(t)COOR_(u) group, where R_(u) is: a C₁ to C₁₂alkyl, optionally substituted with: a C₆ to C₈ aryl optionallysubstituted with a C₁ to C₆ alkyl or an alkoxy; an alkylene; an alkoxy;an alkyne; a halogen; or a 5 or 6 membered heterocycle; a C₆ to C₈ aryl,optionally substituted with: an alkoxy; a halogen; or a C₁ to C₆ alkyl;or a 5 or 6 membered heterocycle; and R_(t) is: a hydrogen; a C₁ to C₆alkyl; a —COR_(x) group, where R_(x) is as defined above; a haloalkyl;or a haloalkoxy; a —NR_(v)SO₂R_(w) group, where R_(v) is: a hydrogen; a—COR_(x), where R_(x) is as defined above; or a C₁ to C₆ alkyl,optionally substituted with: a halogen; a —COR_(x) group, where R_(x) isas defined above; a —OCOR_(x) group, where R_(x) is as defined above; ahydroxy; or an alkoxy; and where R_(w) is: a C₁ to C₆ alkyl optionallysubstituted with: a halogen; a haloalkyl; a C₆ to C₈ aryl; or a 5 or 6membered heterocycle; a C₂ to C₆ alkylene; an alkyl- or dialkyl-aminooptionally substituted with a halogen; a 5 or 6 membered heterocycle; ora 5 or 6 membered heteroaryl optionally substituted with: a C₁ to C₆alkyl; a 5 or 6 membered heterocycle; or

optionally substituted with a C₁ to C₆ alkyl, where R_(y) is a C₁ to C₆alkyl or hydrogen;

where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally substituted witha C₆ to C₈ aryl; a —SR_(x) group, where R_(x) is as defined above; a—SO₂R_(aa) group, where R_(aa) is: a C₁ to C₆ alkyl; an amino group; analkyl- or dialkyl-amino group optionally substituted with a hydroxy or a—COOR_(x) group, where R_(x) is as defined above, or a 5 or 6 memberedheteroaryl; a C₆ to C₈ aryl; and/or a —NHR_(bb) group, where R_(bb) is:

a —C(═S)NH₂ group; or a —PO(OR_(x))₂ group, where R_(x) is as definedabove; or

group, where R_(cc) is: a naphthalene; a 5 or 6 membered heteroaryl;

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing: an alkoxy; a hydroxy; a halogen; a C₁ to C₆ alkyl, optionallysubstituted with a cyano group; an amino optionally substituted with oneor more C₁ to C₆ alkyl(s); a —NHPOR_(x)R_(x), where R_(x) is as definedabove; a —NR_(cc)CONR_(ff)R_(ff) group, where R_(cc) is a hydrogen or aC₁ to C₆ alkyl, optionally substituted with a halogen, and R_(ff) is: ahydrogen; a haloalkyl; a haloalkoxy; a C₁ to C₆ alkyl; or a —COR_(x),where R_(x) is as defined above; a —NR_(gg)COR_(hh) group, where R_(hh)is: a hydrogen; a C₁ to C₆ alkyl optionally substituted with: an alkoxy;a halogen; or an amino optionally substituted with one or more C₁ to C₆alkyl(s); an amino optionally substituted with one or more C₁ to C₆alkyl(s), where the alkyls are optionally substituted with a halogen; a5 or 6 membered heterocycle; a 5 or 6 membered heteroaryl; and R_(gg)is: a hydrogen; a C₁ to C₆ alkyl; a haloalkyl; a haloalkoxy; or a—COR_(x) group, where R_(x) is as defined above; a haloalkyl; 5 or 6membered heterocycle groups; an amino optionally substituted with one ormore C₁ to C₆ alkyl(s); and/or a —NR_(ii)SO₂R_(x) group, where R_(x) isas defined above, and R_(ii) is: a hydrogen; a C₁ to C₆ alkyl; ahaloalkyl; a haloalkoxy; or a —COR_(x) group, where R_(x) is as definedabove; Z is: a C₁ to C₆ alkyl optionally substituted with: an alkoxy;one or more halogen(s); or a C₆ to C₈ aryl; a C₂ to C₆ alkylene; a C₆ toC₈ aryl optionally substituted with an alkoxy or one or more C₁ to C₆alkyl(s); a —COOR_(x) group, where R_(x) is as defined above; or

R is a hydrogen, a halogen or an alkoxy; R₁ is: a hydrogen; a hydroxy; ahalogen; a haloalkyl; a nitro group; a 5 or 6 membered heteroaryl; a 5or 6 membered heterocycle; an alkoxy optionally substituted with: one ormore halogen(s); a C₆ to C₈ aryl; or a 5 or 6 membered heterocycle; a C₆to C₈ aryl optionally substituted with an alkoxy; a —COR_(x) group,where R_(x) is as defined above; a C₁ to C₆ alkyl optionally substitutedwith a dialkyl-amino or a 5 or 6 membered heterocycle; or R₁ joinstogether with R₂ to form:

R₂ is: a nitro group; a hydrogen; a halogen; a hydroxy group; a C₁ to C₆alkyl group, optionally substituted with one or more halogen(s); anamino group; an alkoxy group optionally substituted with: one or morehalogen(s), an —OCOR_(x) group, where R_(x) is as defined above, adialkyl-amino optionally substituted with an alkoxy, a 5 or 6 memberedheterocycle group optionally substituted with a C₁ to C₆ alkyl, a 5 or 6membered heteroaryl group, or a C₆ to C₈ aryl group, a —COOR_(x) group,where R_(x) is as defined above; a haloalkyl; an amide group optionallysubstituted with: a hydroxy group; or a C₆ to C₈ aryl; a 5 or 6 memberedheteroaryl; a —OCOR_(x) group, where R_(x) is as defined above; a—NHCOR_(jj) group, where R_(jj) is: an alkoxy; or an amino optionallysubstituted with one or more C₁ to C₆ alkyl(s); a —OR_(kk) group, whereR_(kk) is a 5 to 6 membered heteroaryl; a —NHSO₂R_(x) group, where R_(x)is as defined above; or R₂ joins together with R₁ to form:

R₃ is: a hydrogen; or —CH₂OCOR_(x), and R_(x) is as defined above;provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, Ris hydrogen, R₁ is hydrogen or hydroxy, R₂ is hydrogen or hydroxy, andR₃ is hydrogen, then Z is: a C₁ to C₆ alkyl substituted with: an alkoxy;one or more halogen(s); or a C₆ to C₈ aryl; a C₂ to C₆ alkylene; a C₆ toC₈ aryl optionally substituted with an alkoxy or one or more C₁ to C₆alkyl(s); a —COOR_(x) group, where R_(x) is as defined above; or

or one or more pharmaceutically acceptable salt(s) thereof; and (ii) oneor more pharmaceutically acceptable excipient(s).
 70. A method fortreating an infection by a virus in a subject in need thereof, whereinthe virus contains an internal ribosome entry site (IRES), comprisingadministering to the subject one or more compound(s) of formula I or apharmaceutical composition comprising one or more compound(s) of formulaI

wherein: X is: a nitro group; a cyano group; a —COR_(a) group, whereR_(a) is: a C₁ to C₆ alkyl; a C₆ to C₈ aryl optionally substituted withan alkoxy or a halogen; or a dialkyl-amino; a —COOR_(x) group, whereR_(x) is a C₁ to C₆ alkyl; a formyl group; a C₆ to C₈ aryl optionallysubstituted with an alkoxy; or a 5 or 6-membered heteroaryl optionallysubstituted with: a C₁ to C₆ alkyl; a C₆ to C₈ aryl optionallysubstituted with an alkoxy or one or more halogen(s); or a 5 to 6membered heteroaryl; Y is: a haloalkyl; a halogen; an amino optionallysubstituted with one or more C₁ to C₆ alkyl(s); a benzofuran; abenzothiophene; a dibenzofuran; a dibenzothiophene; a benzothiazole; anaphthalene; an indole, optionally substituted on the nitrogen with a C₁to C₆ alkyl;

where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as definedabove, or an —SO₂R_(x), where R_(x) is as defined above; or

where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl; a —NHCOR_(e) group,where R_(e) is: a C₁ to C₆ alkyl; or a C₆ to C₈ aryl optionallysubstituted with: a C₁ to C₆ alkyl; an alkoxy; a cyano group; a nitrogroup; or a halogen; a —NHCOOR_(x) group, where R_(x) is as definedabove; a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl; a—NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a hydrogen andR_(h) is a C₆ to C₈ aryl optionally substituted with an alkoxy; a C₁ toC₆ alkyl; a 5 or 6 membered heteroaryl, optionally substituted with: aC₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl; a C₆ to C₈aryl, optionally substituted with —COOR_(x), where R_(x) is as definedabove; or an amino group; a 5 or 6 membered heterocycle optionallysubstituted with: a —COOR_(x) group, where R_(x) is as defined above; ora —NHCOOR_(x) group, where R_(x) is as defined above; a C₆ to C₈ aryl,optionally substituted with one or more of the following: an alkoxy,optionally substituted with: an alkoxy; a hydroxy; one or morehalogen(s); a 5 or 6 membered heterocycle, optionally substituted with:a C₁ to C₆ alkyl; or a hydroxy; an amino group optionally substitutedwith one or more C₁ to C₆ alkyl(s); a —NR_(i)SO₂R_(x) group, where R_(x)is as defined above and R_(i) is: a hydrogen; a C₁ to C₆ alkyl; a—COR_(x) group, where R_(x) is as defined above; a haloalkyl; or ahaloalkoxy; a —NR_(j)COR_(k) group, where R_(k) is: a C₁ to C₆ alkyl; ahydrogen; or an amino optionally substituted with one or more C₁ to C₆alkyl(s); and where R_(j) is: a hydrogen; a C₁ to C₆ alkyl; a —COR_(x)group, where R_(x) is as defined above; a haloalkyl; or a haloalkoxy; a—N═N⁺═N⁻ group; or a —COR₁, where R₁ is a 5 or 6 membered heterocycleoptionally substituted with a hydroxy; an amino optionally substitutedwith one or more C₁ to C₆ alkyl(s); a nitro group; a C₁ to C₆ alkylgroup, optionally substituted with: a —NHSO₂R_(x) group, where R_(x) isas defined above; or a —NR_(x)SO₂R_(x) group, where R_(x) is as definedabove; a haloalkoxy; a halogen; a hydroxy; a —COOR_(x) group, whereR_(x) is as defined above; a —COR_(m) group, where R_(m) is: an aminooptionally substituted with one or more C₁ to C₆ alkyl(s), where the oneor more C₁ to C₆ alkyl(s) is/are optionally substituted with: a hydroxy;a 5 or 6 membered heterocycle; an amino optionally substituted with oneor more C₁ to C₆ alkyls; and/or an alkoxy; a 3 to 7 memberedheterocycle, optionally substituted with a C₁ to C₆ alkyl, optionallysubstituted with a dialkyl-amino; a —NHR_(n) group, where R_(n) is: a—CH₂CONH₂; or a C₆ to C₈ aryl optionally substituted with: an alkyl; oneor more halogen(s); a nitro group; or one or more alkoxy(s); a—NR_(o)COR_(p) group, where R_(p) is: a C₁ to C₆ alkyl optionallysubstituted with: a halogen; an alkoxy; or a C₆ to C₈ aryl; a 5 or 6membered heterocycle; a C₆ to C₈ aryl, optionally substituted with ahalogen; a 5 or 6 membered heteroaryl optionally substituted with one ormore C₁ to C₆ alkyl(s); a hydrogen;

and where R_(o) is: a hydrogen; a C₁ to C₆ alkyl; a —COR_(x) group,where R_(x) is as defined above; a haloalkyl; or a haloalkoxy; a—NR_(q)CONR_(q)R_(r) group, where R_(q) is: a hydrogen; a C₁ to C₆alkyl; a haloalkyl; a haloalkoxy; or a —COR_(x) group, where R_(x) is asdefined above; and where R_(r) is: a C₆ to C₈ aryl optionallysubstituted with:

a C₁ to C₆ alkyl; a haloalkyl; a —OR_(s) group, where R_(s) is a C₆ toC₈ aryl; or a —COOR_(x) group, where R_(x) is as defined above; a C₁ toC₆ alkyl optionally substituted with one or more of the following: ahalogen; an alkylene; a C₆ to C₈ aryl; and/or a —COOR_(x) group, whereR_(x) is as defined above; a —COOR_(x) group, where R_(x) is as definedabove; a —NR_(t)COOR_(u) group, where R_(u) is: a C₁ to C₁₂ alkyl,optionally substituted with: a C₆ to C₈ aryl optionally substituted witha C₁ to C₆ alkyl or an alkoxy; an alkylene; an alkoxy; an alkyne; ahalogen; or a 5 or 6 membered heterocycle; a C₆ to C₈ aryl, optionallysubstituted with: an alkoxy; a halogen; or a C₁ to C₆ alkyl; or a 5 or 6membered heterocycle; and where R_(t) is: a hydrogen; a C₁ to C₆ alkyl;a —COR_(x) group, where R_(x) is as defined above; a haloalkyl; or ahaloalkoxy; a —NR_(v)SO₂R_(w) group, where R_(v) is: a hydrogen; a—COR_(x), where R_(x) is as defined above; or a C₁ to C₆ alkyl,optionally substituted with: a halogen; a —COR_(x) group, where R_(x) isas defined above; a —OCOR_(x) group, where R_(x) is as defined above; ahydroxy; or an alkoxy; and where R_(w) is: a C₁ to C₆ alkyl optionallysubstituted with: a halogen; a haloalkyl; a C₆ to C₈ aryl; or a 5 or 6membered heterocycle; a C₂ to C₆ alkylene; an alkyl- or dialkyl-aminooptionally substituted with a halogen; a 5 or 6 membered heterocycle; ora 5 or 6 membered heteroaryl optionally substituted with: a C₁ to C₆alkyl; a 5 or 6 membered heterocycle; or

optionally substituted with a C₁ to C₆ alkyl, where R_(y) is a C₁ to C₆alkyl or hydrogen;

where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally substituted witha C₆ to C₈ aryl; a —SR_(x) group, where R_(x) is as defined above; a—SO₂R_(aa) group, where R_(aa) is: a C₁ to C₆ alkyl; an amino group; analkyl- or dialkyl-amino group optionally substituted with a hydroxy or a—COOR_(x) group, where R_(x) is as defined above; or a 5 or 6 memberedheteroaryl; a C₆ to C₈ aryl; and/or a —NHR_(bb) group, where R_(bb) is:

a —C(═S)NH₂ group; or a —PO(OR_(x))₂ group, where R_(x) is as definedabove; or

group, where R_(cc) is: a naphthalene; a 5 or 6 membered heteroaryl;

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing: an alkoxy; a hydroxy; a halogen; a C₁ to C₆ alkyl, optionallysubstituted with a cyano group; an amino optionally substituted with oneor more C₁ to C₆ alkyl(s); a —NHPOR_(x)R_(x), where R_(x) is as definedabove; a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen or aC₁ to C₆ alkyl, optionally substituted with a halogen, and R_(ff) is: ahydrogen; a haloalkyl; a haloalkoxy; a C₁ to C₆ alkyl; or a —COR_(x),where R_(x) is as defined above; a —NR_(gg)COR_(hh) group, where R_(hh)is: a hydrogen; a C₁ to C₆ alkyl optionally substituted with: an alkoxy;a halogen; or an amino optionally substituted with one or more C₁ to C₆alkyl(s); an amino optionally substituted with one or more C₁ to C₆alkyl(s), where the alkyls are optionally substituted with a halogen; a5 or 6 membered heterocycle; a 5 or 6 membered heteroaryl; and R_(gg)is: a hydrogen; a C₁ to C₆ alkyl; a haloalkyl; a haloalkoxy; or a—COR_(x) group, where R_(x) is as defined above; a haloalkyl; 5 or 6membered heterocycle groups; an amino optionally substituted with one ormore C₁ to C₆ alkyl(s); and/or a —NR_(ii)SO₂R_(x) group, where R_(x) isas defined above, and R_(ii) is: a hydrogen; a C₁ to C₆ alkyl; ahaloalkyl; a haloalkoxy; or a —COR_(x) group, where R_(x) is as definedabove; Z is: a C₁ to C₆ alkyl optionally substituted with: an alkoxy;one or more halogen(s); or a C₆ to C₈ aryl; a C₂ to C₆ alkylene; a C₆ toC₈ aryl optionally substituted with an alkoxy or one or more C₁ to C₆alkyl(s); a —COOR_(x) group, where R_(x) is as defined above; or

R is a hydrogen, a halogen or an alkoxy; R₁ is: a hydrogen; a hydroxy; ahalogen; a haloalkyl; a nitro group; a 5 or 6 membered heteroaryl; a 5or 6 membered heterocycle; an alkoxy optionally substituted with: one ormore halogen(s); a C₆ to C₈ aryl; or a 5 or 6 membered heterocycle; a C₆to C₈ aryl optionally substituted with an alkoxy; a —COR_(x) group,where R_(x) is as defined above; a C₁ to C₆ alkyl optionally substitutedwith a dialkyl-amino or a 5 or 6 membered heterocycle; or R₁ joinstogether with R₂ to form:

R₂ is: a nitro group; a hydrogen; a halogen; a hydroxy group; a C₁ to C₆alkyl group, optionally substituted with one or more halogen(s); anamino group; an alkoxy group optionally substituted with: one or morehalogen(s); an —OCOR_(x) group, where R_(x) is as defined above; adialkyl-amino optionally substituted with an alkoxy; a 5 or 6 memberedheterocycle group optionally substituted with a C₁ to C₆ alkyl; a 5 or 6membered heteroaryl group; or a C₆ to C₈ aryl group; a —COOR_(x) group,where R_(x) is as defined above; a haloalkyl; an amide group optionallysubstituted with: a hydroxy group; or a C₆ to C₈ aryl; a 5 or 6 memberedheteroaryl; a —OCOR_(x) group, where R_(x) is as defined above; a—NHCOR_(jj) group, where R_(jj) is: an alkoxy; or an amino optionallysubstituted with one or more C₁ to C₆ alkyl(s); a —OR_(kk) group, whereR_(kk) is a 5 to 6 membered heteroaryl; a —NHSO₂R_(x) group, where R_(x)is as defined above; or R₂ joins together with R₁ to form:

R₃ is: a hydrogen; or —CH₂OCOR_(x), where R_(x) is as defined above; orone or more pharmaceutically acceptable salt(s) thereof
 71. A method fortreating a Hepatitis C viral (HCV) infection in a subject in needthereof, comprising administering to the subject one or more compound(s)of formula I or a pharmaceutical composition comprising one or morecompound(s) of formula I

wherein: X is: a nitro group; a cyano group; a —COR_(a) group, whereR_(a) is: a C₁ to C₆ alkyl; a C₆ to C₈ aryl optionally substituted withan alkoxy or a halogen; or a dialkyl-amino; a —COOR_(x) group, whereR_(x) is a C₁ to C₆ alkyl; a formyl group; a C₆ to C₈ aryl optionallysubstituted with an alkoxy; or a 5 or 6-membered heteroaryl optionallysubstituted with: a C₁ to C₆ alkyl; a C₆ to C₈ aryl optionallysubstituted with an alkoxy or one or more halogen(s); or a 5 to 6membered heteroaryl; Y is: a haloalkyl; a halogen; an amino optionallysubstituted with one or more C₁ to C₆ alkyl(s); a benzofuran; abenzothiophene; a dibenzofuran; a dibenzothiophene; a benzothiazole; anaphthalene; an indole, optionally substituted on the nitrogen with a C₁to C₆ alkyl;

where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as definedabove, or an —SO₂R_(x), where R_(x) is as defined above;

where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl; a —NHCOR_(e) group,where R_(e) is: a C₁ to C₆ alkyl; a C₆ to C₈ aryl optionally substitutedwith: a C₁ to C₆ alkyl; an alkoxy; a cyano group; a nitro group; or ahalogen; a —NHCOOR_(x) group, where R_(x) is as defined above; a—CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl; a —NR_(g)R_(h) group,where R_(g) is a C₁ to C₆ alkyl or a hydrogen and R_(h) is a C₆ to C₈aryl optionally substituted with an alkoxy; a C₁ to C₆ alkyl; a 5 or 6membered heteroaryl, optionally substituted with: a C₁ to C₆ alkyl,optionally substituted with a C₆ to C₈ aryl; a C₆ to C₈ aryl, optionallysubstituted with —COOR_(x), where R_(x) is as defined above; or an aminogroup; a 5 or 6 membered heterocycle optionally substituted with: a—COOR_(x) group, where R_(x) is as defined above; or a —NHCOOR_(x)group, where R_(x) is as defined above; a C₆ to C₈ aryl, optionallysubstituted with one or more of the following: an alkoxy, optionallysubstituted with: an alkoxy; a hydroxy; one or more halogen(s); a 5 or 6membered heterocycle, optionally substituted with: a C₁ to C₆ alkyl; orhydroxy; an amino group optionally substituted with one or more C₁ to C₆alkyl(s); a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above andR_(i) is: a hydrogen; a C₁ to C₆ alkyl; a —COR_(x) group, where R_(x) isas defined above; a haloalkyl; or a haloalkoxy; a —NR_(j)COR_(k) group,where R_(k) is: a C₁ to C₆ alkyl; a hydrogen; or an amino optionallysubstituted with one or more C₁ to C₆ alkyl(s); and R_(j) is: ahydrogen; a C₁ to C₆ alkyl; a —COR_(x) group, where R_(x) is as definedabove; a haloalkyl; or a haloalkoxy; a —N═N⁺═N⁻ group; or a —COR₁, whereR₁ is a 5 or 6 membered heterocycle optionally substituted with ahydroxy; an amino optionally substituted with one or more C₁ to C₆alkyl(s); a nitro group; a C₁ to C₆ alkyl group, optionally substitutedwith: a —NHSO₂R_(x) group, where R_(x) is as defined above; or a—NR_(x)SO₂R_(x) group, where R_(x) is as defined above; a haloalkoxy; ahalogen; a hydroxy; a —COOR_(x) group, where R_(x) is as defined above;a —COR_(m) group, where R_(m) is: an amino optionally substituted withone or more C₁ to C₆ alkyl(s), where the one or more C₁ to C₆ alkyl(s)is/are optionally substituted with: a hydroxy; a 5 or 6 memberedheterocycle; an amino optionally substituted with one or more C₁ to C₆alkyl(s); an alkoxy; a 3 to 7 membered heterocycle, optionallysubstituted with a C₁ to C₆ alkyl, optionally substituted with adialkyl-amino; or a —NHR_(n) group, where R_(n) is: a —CH₂CONH₂; or a C₆to C₈ aryl optionally substituted with: an alkyl; one or morehalogen(s); a nitro group; or one or more alkoxy(s); a —NR_(o)COR_(p)group, where R_(p) is: a C₁ to C₆ alkyl optionally substituted with: ahalogen; an alkoxy; or a C₆ to C₈ aryl; a 5 or 6 membered heterocycle; aC₆ to C₈ aryl, optionally substituted with a halogen; a 5 or 6 memberedheteroaryl optionally substituted with one or more C₁ to C₆ alkyl(s); ahydrogen;

and where R_(o) is: a hydrogen; a C₁ to C₆ alkyl; a —COR_(x) group,where R_(x) is as defined above; a haloalkyl; or a haloalkoxy; a—NR_(q)CONR_(q)R_(r) group, where R_(q) is: a hydrogen; a C₁ to C₆alkyl; a haloalkyl; a haloalkoxy; or a —COR_(x) group, where R_(x) is asdefined above; and where R_(r) is: a C₆ to C₈ aryl optionallysubstituted with:

a C₁ to C₆ alkyl; a haloalkyl; a —OR_(s) group, where R_(s) is a C₆ toC₈ aryl; or a —COOR_(x) group, where R_(x) is as defined above; a C₁ toC₆ alkyl optionally substituted with one or more of the following: ahalogen; an alkylene; a C₆ to C₈ aryl; and/or a —COOR_(x) group, whereR_(x) is as defined above; a —COOR_(x) group, where R_(x) is as definedabove; a —NR_(t)COOR_(u) group, where R_(u) is: a C₁ to C₁₂ alkyl,optionally substituted with: a C₆ to C₈ aryl optionally substituted witha C₁ to C₆ alkyl or an alkoxy; an alkylene; an alkoxy; an alkyne; ahalogen; or a 5 or 6 membered heterocycle; a C₆ to C₈ aryl, optionallysubstituted with: an alkoxy; a halogen; or a C₁ to C₆ alkyl; or a 5 or 6membered heterocycle; and R_(t) is: a hydrogen; a C₁ to C₆ alkyl; a—COR_(x) group, where R_(x) is as defined above; a haloalkyl; or ahaloalkoxy; a —NR_(v)SO₂R_(w) group, where R_(v) is: a hydrogen; a—COR_(x), where R_(x) is as defined above; or a C₁ to C₆ alkyl,optionally substituted with: a halogen; a —COR_(x) group, where R_(x) isas defined above; a —OCOR_(x) group, where R_(x) is as defined above; ahydroxy; or an alkoxy; and where R_(w) is: a C₁ to C₆ alkyl optionallysubstituted with: a halogen; a haloalkyl; a C₆ to C₈ aryl; or a 5 or 6membered heterocycle; a C₂ to C₆ alkylene; an alkyl- or dialkyl-aminooptionally substituted with a halogen; a 5 or 6 membered heterocycle; ora 5 or 6 membered heteroaryl optionally substituted with: a C₁ to C₆alkyl; a 5 or 6 membered heterocycle; or

optionally substituted with a C₁ to C₆ alkyl, where R_(y) is a C₁ to C₆alkyl or hydrogen;

where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally substituted witha C₆ to C₈ aryl; a —SR_(x) group, where R_(x) is as defined above; a—SO₂R_(aa) group, where R_(aa) is: a C₁ to C₆ alkyl; an amino group; analkyl- or dialkyl-amino group optionally substituted with a hydroxy or a—COOR_(x) group, where R_(x) is as defined above; or a 5 or 6 memberedheteroaryl; a C₆ to C₈ aryl; and/or a —NHR_(bb) group, where R_(bb) is:

a —C(═S)NH₂ group; or a —PO(OR_(x))₂ group, where R_(x) is as definedabove;

group, where R_(cc) is: a naphthalene; a 5 or 6 membered heteroaryl;

a C₆ to C₈ aryl, optionally substituted with one or more of thefollowing: an alkoxy; a hydroxy; a halogen; a C₁ to C₆ alkyl, optionallysubstituted with a cyano group; an amino optionally substituted with oneor more C₁ to C₆ alkyl(s); a —NHPOR_(x)R_(x), where R_(x) is as definedabove; a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen or aC₁ to C₆ alkyl, optionally substituted with a halogen, and R_(ff) is: ahydrogen; a haloalkyl; a haloalkoxy; a C₁ to C₆ alkyl; or a —COR_(x),where R_(x) is as defined above; a —NR_(gg)COR_(hh) group, where R_(hh)is: a hydrogen; a C₁ to C₆ alkyl optionally substituted with: an alkoxy;a halogen; or -an amino optionally substituted with one or more C₁ to C₆alkyl(s); an amino optionally substituted with one or more C₁ to C₆alkyl(s), where the one or more C₁ to C₆ alkyl(s) is/are optionallysubstituted with a halogen; a 5 or 6 membered heterocycle; a 5 or 6membered heteroaryl; and R_(gg) is: a hydrogen; a C₁ to C₆ alkyl; ahaloalkyl; a haloalkoxy; or a —COR_(x) group, where R_(x) is as definedabove; a haloalkyl; 5 or 6 membered heterocycle groups; an aminooptionally substituted with one or more C₁ to C₆ alkyl(s); and/or a—NR_(ii)SO₂R_(x) group, where R_(x) is as defined above, and R_(ii) is:a hydrogen; a C₁ to C₆ alkyl; a haloalkyl; a haloalkoxy; or a —COR_(x)group, where R_(x) is as defined above; Z is: a C₁ to C₆ alkyloptionally substituted with: an alkoxy; one or more halogen(s); or a C₆to C₈ aryl; a C₂ to C₆ alkylene; a C₆ to C₈ aryl optionally substitutedwith an alkoxy or one or more C₁ to C₆ alkyl(s); a —COOR_(x) group,where R_(x) is as defined above; or

R is a hydrogen, a halogen or an alkoxy; R₁ is: a hydrogen; a hydroxy; ahalogen; a haloalkyl; a nitro group; a 5 or 6 membered heteroaryl; a 5or 6 membered heterocycle; an alkoxy optionally substituted with: one ormore halogen(s); a C₆ to C₈ aryl; or a 5 or 6 membered heterocycle; a C₆to C₈ aryl optionally substituted with an alkoxy; a —COR_(x) group,where R_(x) is as defined above; a C₁ to C₆ alkyl optionally substitutedwith a dialkyl-amino or a 5 or 6 membered heterocycle; or R₁ joinstogether with R₂ to form:

R₂ is: a nitro group; a hydrogen; a halogen; a hydroxy group; a C₁ to C₆alkyl group, optionally substituted with one or more halogen(s); anamino group; an alkoxy group optionally substituted with: one or morehalogen(s); an —OCOR_(x) group, where R_(x) is as defined above; adialkyl-amino optionally substituted with an alkoxy; a 5 or 6 memberedheterocycle group optionally substituted with a C₁ to C₆ alkyl; a 5 or 6membered heteroaryl group; or a C₆ to C₈ aryl group; a —COOR_(x) group,where R_(x) is as defined above; a haloalkyl; an amide group optionallysubstituted with: a hydroxy group; or a C₆ to C₈ aryl; a 5 or 6 memberedheteroaryl; a —OCOR_(x) group, where R_(x) is as defined above; a—NHCOR_(jj) group, where R_(jj) is: an alkoxy; or an amino optionallysubstituted with one or more C₁ to C₆ alkyl(s); a —OR_(kk) group, whereR_(kk) is a 5 to 6 membered heteroaryl; a —NHSO₂R_(x) group, where R_(x)is as defined above; or R₂ joins together with R₁ to form:

R₃ is: a hydrogen; or —CH₂OCOR_(x), where R_(x) is as defined above; orone or more pharmaceutically acceptable salt(s) thereof.
 72. A compoundof formula IIIb

wherein: X is hydrogen; Y is: a 5 or 6 membered heteroaryl, optionallysubstituted with a C₆ to C₈ aryl, optionally substituted with —COOR_(x),where R_(x) is as defined above; or a C₆ to C₈ aryl, optionallysubstituted with one or more of the following: an amino optionallysubstituted with one or more C₁ to C₆ alkyl(s); a halogen; a hydroxy; a—COR_(m) group, where R_(m) is an amino optionally substituted with oneor more C₁ to C₆ alkyl(s); a —NR_(o)COR_(p) group, where R_(p) is a C₁to C₆ alkyl optionally substituted with an alkoxy, and where R_(o) is ahydrogen; a —NR_(q)CONR_(q)R_(r) group, where R_(q) is hydrogen andwhere R_(r) is a C₁ to C₆ alkyl; a —NR_(t)COOR_(u) group, where R_(t) ishydrogen, and where R_(u) is a C₁ to C₁₂ alkyl, optionally substitutedwith: a C₆ to C₈ aryl; a halogen; or a 5 or 6 membered heterocycle; a—NR_(v)SO₂R_(w) group, where R_(v) is hydrogen and where R_(w) is: a C₁to C₆ alkyl; or an alkyl- or dialkyl-amino;

where R_(z) is hydrogen or a C₁ to C₆ alkyl; a —SO₂R_(aa) group, whereR_(aa) is: an amino group; or an alkyl- or dialkyl-amino group; or a—NHR_(bb) group, where R_(bb) is a —PO(OR_(x))₂ group, where R_(x) is asdefined above; Z is: a C₁ to C₆ alkyl; or a —COOR_(x) group, where R_(x)is as defined above; R is a hydrogen, R₁ is: a hydrogen; a 5 or 6membered heterocycle; or an alkoxy optionally substituted with: one ormore halogen(s); or a 5 or 6 membered heterocycle; R₂ is: a hydrogen; ahydroxy group; a C₁ to C₆ alkyl group, optionally substituted with oneor more halogen(s); an alkoxy group optionally substituted with: one ormore halogen(s); a 5 or 6 membered heterocycle group optionallysubstituted with a C₁ to C₆ alkyl; or a 5 or 6 membered heteroarylgroup; a —COOR_(x) group, where R_(x) is as defined above; an amidegroup; a 5 or 6 membered heteroaryl; or a —OR_(kk) group, where R_(kk)is a 5 to 6 membered heteroaryl; and R₃ is a hydrogen.
 73. The compoundof claim 72, wherein: X is: hydrogen; Y is: a C₆ to C₈ aryl, substitutedwith —NR_(t)COOR_(u) group, where R_(t) is hydrogen, and where R_(u) isa C₁ to C₁₂ alkyl; Z is: a C₁ to C₆ alky; R is: a hydrogen; R₁ is: ahydrogen; R₂ is: a —OR_(kk) group, where R_(kk) is a 5 to 6 memberedheteroaryl; R₃ is: a hydrogen.
 74. A compound which is selected from thecompound range: 866-1329, 1484-2127, 2129-2545.
 75. The compound ofclaim 74 selected from: